JP2020516625A - Method for treating NK1 antagonist combination and synucleinopathies - Google Patents

Abstract

The present invention provides a therapeutically effective 6-propylamino-4,5,6,7-tetrahydro-to act without the typical adverse effects caused by pramipexole dihydrochloride monohydrate when administered alone. 6-Propylamino-4,5,6, to facilitate the treatment of patients with synucleinopathies by allowing a daily dose of 1,3-benzothiazol-2-amine The use of NK1 antagonists in combination with 7-tetrahydro-1,3-benzothiazol-2-amine is described.

Description

RELATED APPLICATION This application claims the benefit of US Provisional Patent Application No. 62/483,555, filed April 10, 2017, the disclosure of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION The present invention relates to the field of treatment of synucleinopathy, a neurodegenerative disorder of the human central nervous system, in particular of neurotoxic processes by oligomerization and aggregation of α-synuclein.

OBJECT OF THE INVENTION The present invention provides 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, and a neurokinin receptor. Body subtype-1 antagonists (“NK1 antagonists”) and pharmaceutical combinations (including fixed dose combinations), and synucleinopathies, especially in blood It relates to its use for treating the CNS neurotoxic effect of α-synuclein in human subjects exhibiting an abnormal plasma exosome/total α-synuclein ratio.

Definitions-"CNS": central nervous system-"IR": immediate release of active ingredient from composition-"ER": sustained release of active ingredient from composition-"GI": gastrointestinal-AE": Adverse effects-"SNCA gene": synuclein-α or α-synuclein gene-"MSA": multiple system atrophy-"PD": Parkinson's disease-"LBD": dementia with Lewy bodies-"AD": Alzheimer's disease- “Synucleinosis”: A disease characterized by abnormal accumulation, processing, and diffusion of alpha-synuclein (a-synuclein) in the brain. That is, α-synuclein is deposited in the central, peripheral and autonomic nervous systems. Synucleinopathies (also called α-synucleinopathies) include, but are not limited to, Parkinson's disease, dementia with Lewy bodies or dementia with Lewy bodies (LBD or DLB), Alzheimer's disease, Lewy body variants of AD, Neurodegenerative diseases, including multiple system atrophy, neurodegeneration with iron accumulation in the brain, and Parkinson's disease associated with glucocerebrosidase (GBA) mutations.
"TTS": transdermal therapeutic system.
-"Effective daily dose of NK1 antagonist": as used herein, this phrase is the dose of the NK1 antagonist that is present during cancer chemotherapy according to current protocols for the treatment. Refers to a dose that is at least comparable to the dose for preventing or treating nausea and vomiting in pediatric or adult patients. The daily dose is usually 1 mg to 600 mg.
“6-Propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine”: a chiral chemical compound available as a racemate, chemically (R,S)-6-propyl. Amino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, (R)-stereoisomer is chemically (R)-6-propylamino-4,5,6,6. 7-Tetrahydro-1,3-benzothiazol-2-amine (“dexpramipexole”, INN), and (S)-stereoisomers are chemically (S)-6-propylamino-4,5,6. , 7-Tetrahydro-1,3-benzothiazol-2-amine ("Pramipexole", INN). Each of these three chemical substances is a basic substance that can be separated as an acid addition salt and a solvate thereof. Pramipexole dihydrochloride monohydrate is also known in its USAN “Pramipexole Hydrochloride”. As used herein, "6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine" refers to pramipexole, racemate, and pramipexole/dexpramipexole unless otherwise stated. A general term for members selected from the group consisting of mixtures.
-"(R)/(S)-mixture": this term refers to the dexpramipexole/pramipexole physical mixture used as active ingredient according to the invention.
“(S)-Enantiomer”: This term refers to 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine dose (daily or per unit form). 6-Propylamino-4,5,6,7-tetrahydro-1,3-benzo, as used herein in connection, is the major cause of the dopaminergic effects suppressed by NK1 antagonists. In thiazol-2-amine, it represents the (S)-stereoisomer contained in said dose. More specifically, the S-enantiomer is used to represent the S-stereoisomer present in the racemate or a pharmaceutically acceptable salt thereof, as well as pramipexole used alone. For purposes of distinction, it is used herein to refer to pramipexole or its pharmaceutically acceptable salt present as the (S)-component in the (R)/(S) mixture.
The term "6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine", "(R)-6-propylamino-4,5,6,7-tetrahydro- 1,3-benzothiazol-2-amine", "dexpramipexole", "pramipexole", "(S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-" “Amine”, “(S)-enantiomer”, “racemate” and “(R)/(S)-mixture” (unless otherwise stated) include the free base and pharmaceutically acceptable salts thereof. And the relative dose (daily or per unit form) is given in equivalent amounts of pramipexole dihydrochloride monohydrate.
“Effective daily dose of pramipexole” or “(S)-effective daily dose of enantiomer”: Effective daily dose of pramipexole or its pharmaceutically acceptable salts and solvates for one child or adult. And a dose at least equivalent to the dose of pramipexole dihydrochloride monohydrate approved for the treatment of PD.
“Effective amount of pramipexole per unit form” or “Effective amount of (S)-enantiomer per unit form”: at least per unit form of pramipexole dihydrochloride monohydrate approved for PD treatment. Per unit form of pramipexole or a pharmaceutically acceptable salt or solvate thereof. More specifically, the unit form amount corresponds to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate. As used above and herein, "pramipexole" and "(S)-enantiomer" refer to the same chemical entity, but the term "(S)-enantiomer" generally refers to racemates and (R )/(S)-used to describe the composition of the mixture.

Α-synuclein, a 140 amino acid protein encoded by the SNCA gene, is abundantly expressed in the human brain and is found predominantly in nerve endings, especially in the cortex, hippocampus, substantia nigra and cerebellum. It contributes locally to the regulation of neurotransmitter release, is excreted in the blood (Marques and Outeiro, 2012) and is included in CNS-derived exosomes (Shi et al., 2014).

Under normal circumstances, this soluble protein forms a stable folded tetramer that resists aggregation. However, in certain pathological conditions, for unknown reasons, α-synuclein oligomerizes and aggregates (due to fibril formation or “fibrillization”), and thus its conformation in blood. It causes an abnormal change in the tertiary toxic three-dimensional structure excreted in.

Oligomerization and aggregation of α-synuclein is associated with synucleinopathies, especially PD, LBD, Parkinson's disease disorders associated with glucocerebrosidase gene (GBA) mutations, MSA, some forms of Alzheimer's disease, and It is believed to be the cause of several other disorders collectively referred to as "pathies." Alpha-synuclein is a ubiquitous protein that is especially abundant in the brain and has been hypothesized to play a central role in the pathogenesis of Parkinson's disease (PD), Alzheimer's disease, and other neurodegenerative disorders (Kim et al., 2004). ).

An abnormal plasma exosome/total α-synuclein ratio in the blood of patients is a diagnostic feature of synucleinopathies.

PD is a common neurodegenerative disorder of the human CNS, first described by James Parkinson in 1817. PD has three major clinical manifestations: resting tremor, bradykinesia, and muscle stiffness. In addition, postural instability and various neurobehavioral disorders may occur. In the United States alone, it is estimated that more than one million individuals suffer from this disability-inhibiting disability. Moreover, the prevalence of PD continues to increase with the general aging of the American population. Currently, the symptoms of Parkinson's disease are believed to primarily reflect the progressive loss of dopaminergic neurons within the nigrostriatal system. The origin of this degenerative process is not completely understood, but it appears that at the moment it is involved in the production of aberrant neurotoxic species by mistreatment of α-synuclein.

Dementia with Lewy bodies (Lewy body dementia, LBD) is one of the most common types of progressive dementia. Central features of LBD include progressive cognitive decline, hallucinations, and Parkinson's motor symptoms such as slowness of movement, difficulty walking, and muscle stiffness. Some people suffer from depression. The symptoms of LBD are caused by the selective loss of neurons, probably as a result of mistreatment of synuclein and associated with Lewy body accumulation (spherical synuclein accumulation of degenerating neurons). Researchers have not elucidated why α-synuclein accumulates as Lewy bodies, or how synuclein species can cause the symptoms of LBD. The formation of LBD is believed to be a marker for PD. However, LBD has also been observed in up to 60% of sporadic and familial cases of Alzheimer's disease (AD) (Al-Mansoor et al., 2013). Therefore, it is strongly suggested that the aggregation of α-synuclein is an important step in the development of neurodegenerative diseases (Al-Mansoor et al., 2013).

Sporadic PD or brainstem-predominant LBD, and Lewy body dementia (DLB) are the two most common a-synucleinopathies, with widespread α-synuclein deposition in the central, peripheral, and autonomic nervous systems. It is a progressive multisystem neurodegenerative disorder with frequent development (Jellinger KA 2008a). Reportedly, there is significant clinical and pathological overlap between PD (with or without dementia) and DLB (or LBD), both of which are often associated with variable Alzheimer's-type pathology, Braak LB stage 5 And 6 (Jellinger KA 2008a). Dementia often does not correlate with the advanced stage of LB pathology, but may also be associated with incidental Alzheimer's lesions or mixed pathologies (Jellinger KA, 2008a).

Alzheimer's disease (AD) has been reported to be characterized by β-amyloid peptide, phosphorylated tau protein (3- and 4-repeat tau) and α-synuclein (aSyn) deposition (Jellinger KA, 2008b). Lewy body disorders (LBD), such as sporadic Parkinson's disease (PD) and dementia with Lewy bodies (DLB), show aSyn-positive deposits on neurons, neurites, glia, and presynaptic terminals, but frontal Temporal dementia refers to tau-positive and tau-negative, ubiquitin and TDP-43 positive nerve and glial inclusions (Jellinger KA, 2008b). Molecular interactions between major proteins that can occur in the same brain with different distribution patterns have been demonstrated by different phenotypes and mixed lesions, such as AD with aSyn pathology of the brainstem and amygdala, PD and DLB with AD lesions, and various deposits. Is associated with frontotemporal dementia with a mixture of substances, while other molecular interactions are characterized by one major pathology without other lesions (eg, neurofibrillary tangles). (Tangle-predominant) dementia, pure PD, brainstem dominant LBD) (Jellinger KA, 2008b).

MSA with orthostatic hypotension is the current term for a neurological disease formerly called Shy-Drager syndrome. MSA is a progressive disorder of the central and autonomic nervous system, characterized by orthostatic hypotension (an excessive decrease in blood pressure during standing), causing dizziness and syncope. Multiple system atrophy can occur without orthostatic hypotension, but with urinary tract involvement (urgency/incontinence) instead. Neurologists refer to this disorder as three types: Parkinson's disease type, which includes symptoms of Parkinson's disease such as slow movement, stiff muscles, and tremor; cerebellar type that causes problems with coordination and speech; Parkinson's syndrome. It is classified as a composite type that includes both symptoms of cerebellar failure. Problems of urinary incontinence, constipation, and male impotence occur early in the disease. Other symptoms include generalized weakness, diplopia or other visual disorders, dyspnea and dysphagia, sleep disorders, decreased sweating. This disease is similar to other diseases, so a correct diagnosis can take years.

Mutations in the glucocerebrosidase gene (GBA) can cause autosomal recessive disorder Gaucher disease. Evidence from different strains suggests that mutant GBA may be a risk factor for Parkinson's disease. GBA mutations are currently considered to be the single greatest risk factor for developing idiopathic PD. Clinically, imagingly and pharmacologically, GBA PD is nearly identical to idiopathic PD (O'Regan et al., 2017). The molecular mechanism leading to an increased PD risk of this GBA mutation carrier has not been fully elucidated but has been shown to be associated with synuclein accumulation (Soria et al., 2017).

Less commonly, some other disorders are also considered synucleinopathies. These disorders include several cases of Hallerfolden-Spatz syndrome, neuroaxonal dystrophy, and traumatic brain injury. In the case of Hallerfolden-Spatz syndrome, symptoms include parkinsonism, dystonia, dysphagia/dysarthria, limb rigidity/stiffness, dementia, and spasticity.

Many now believe that the processes that lead to synuclein aggregation are central to the nerve damage and destruction that occurs in these disorders.

The mechanism of aggregation in these synucleinopathies remains unclear. Current evidence suggests that the conversion of the α-helical structure to the β-sheet conformation and subsequent oligomerization may be a precursor of virulence and aggregation of synuclein. These properties resemble the aberrant processing of prion proteins, which can also have strong neurotoxicity. Phosphorylation of α-synuclein at the serine 129 residue has been implicated as a contributing factor (Chen et al., 2016). According to the authors, the prion form of alpha synuclein may be the causative agent of multiple system atrophy, among others. Prions are small proteins that have the potential to misfold, oligomerize, aggregate, and spread to other cells. The result in the brain is a deep, diffuse, neurotoxic process.

Therefore, inhibiting synuclein misfolding, oligomerization and aggregation is beneficial in slowing or even arresting the progression of synucleinopathy disorders.

As described above, α-synuclein is easily excreted in the extracellular space and has been identified in cerebrospinal fluid, blood, and saliva (Marques and Outeiro, 2012). Although the mechanism of α-synuclein secretion is not fully understood, in tests, at least a portion of α-synuclein is secreted in association with exosomes, 40-100 nm membrane vesicles of endocytic origin. It has been demonstrated (Shi et al., 2014). Plasma exosome alpha-synuclein has been shown to significantly correlate with disease severity (Shi et al., 2014), and plasma exosome alpha-synuclein can help monitor disease progression. Similarly, levels of exosome α-synuclein correlated with the extent of damage in cross-section samples obtained from LBD patients (Stuendl et al., 2016).

Based on the above, drugs that reduce plasma exosomes/total α-synuclein should slow or even stop the neurodegenerative process associated with synucleinopathies.

Various compositions have been proposed for the treatment of PD-related synucleinopathies and related disorders that target the synuclein aggregation pathway. The discovery process primarily involves cellular and animal models of prion and synuclein-induced neurodegeneration (Prusiner et al., 2015). Unfortunately, none of these models have been validated and all are considered relatively uncertain predictors of efficacy in humans. Nevertheless, these models continue to be widely used in the absence of more reliable discovery techniques.

The drugs currently proposed for study include, for example, (S)-6-propylamino-4,5,6,7-tetrahydro-1,3-used alone or in combination with various drugs. Included are small molecules such as benzothiazol-2-amine (pramipexole) and its analogs.

Pramipexole is a synthetic aminothiazole derivative described in US Pat. No. 4,886,812, the entire contents of which are incorporated herein by reference. Pramipexole, a non-ergoline class dopamine autoreceptor antagonist (Schneider et al. 1987), was approved as a symptomatic treatment for Parkinson's disease (PD) after the late 1990s, 0.375 mg/day to 4.5 mg/day. Is administered in 3 equal divided doses (Mirapex package insert, July 2016). Pramipexole is an immediate release tablet containing 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, and 1.5 mg pramipexole dihydrochloride monohydrate; and 4.5 mg pramipexole dihydrochloride monohydrate. Provided in sustained release tablets.

Although pramipexole is widely used to alleviate the symptoms of Parkinson's disease, it has been the subject of extensive investigation because of its potential as a disease modifying agent.

Pramipexole has been reported to reduce synuclein oligomer formation in vitro (Ono et al., 2013). Related studies suggest that pramipexole inhibits the toxic effects of rotenone on dopaminergic neurons in the mouse PD model, while reducing the immunoreactivity of α-synuclein. Moreover, pramipexole reduces the in vitro oligomerization of human wild-type α-synuclein by H ₂ O ₂ and cytochrome c (Inden et al., 2009). Pramipexole has also been observed to inhibit the aggregation of α-synuclein in human neuroblastoma SH-SY5Y cells (Kakimura et al., 2001). Importantly, the relative expression of α-synuclein in serum exosomes has been shown to decrease during pramipexole treatment of PD patients (Luo et al., 2016).

Unfortunately, the limitations associated with administration of pramipexole to patients with synucleinopathies complicate their use at the potentially high neuroprotective doses predicted in some animal models. First, the mechanisms that explain the putative beneficial effects of pramipexole on synuclein-related neurotoxicity have not been fully elucidated. Second, the effects in animal model studies tend to be small in magnitude, occurring only at relatively high doses. Both situations were also observed in the above report of pramipexole-induced changes in exosome synuclein in PD patients, with administration of the maximum (4.5 mg/day) recommended/approved dose of pramipexole (Mirapex package insert; 2016). Revised in July).

According to a report by Luo et al. (2016), treatment of patients with Parkinson's disease with pramipexole showed relative expression of α-synuclein (compared to pretreatment values) at therapeutic doses approved for treatment of motor symptoms of PD. However, the magnitude of the effect was small. Higher doses of pramipexole may have been more effective, but side effects such as vomiting and severe nausea prevent use of higher doses. For example, Corrigan et al. (2000) found that a dose of 5 mg/day of pramipexole was only slightly higher than the maximum recommended dose of 4.5 mg/day (Pramipexole FDA approved package insert) but caused nausea in 76% of patients. , Reported that it caused vomiting in 39% of patients. Moreover, 36% of patients failed to complete the study, probably due to intolerant GI adverse events.

Recently, it has started to be reported that pramipexole can exert a neuroprotective effect in various in vitro cell models of PD and animal models in vivo. The mechanism by which these protective effects occur remains unclear. Unfortunately, the protective effect of pramipexole in animal models is generally small, requiring higher doses than are considered safe and tolerable for human administration. Therefore, an approved dose of pramipexole for the treatment of motor symptoms of PD failed to demonstrate neuroprotective (ie disease modifying) activity in a randomized controlled clinical trial in 535 PD patients (Schapira et al., 2013). That is not surprising.

A medicament comprising a therapeutically effective amount of dexpramipexol or a pharmaceutically acceptable salt and solvate thereof and a therapeutically effective amount of pramipexole or a pharmaceutically acceptable salt and solvate thereof, which is useful for treating PD An (R)/(S)-mixture consisting of a composition is disclosed in US Patent Application Publication No. 2008/0014259, the entire contents of which are incorporated herein by reference.

According to US Patent Application Publication No. 2008/0014259, both enantiomers accumulate in brain cells, spinal cord, and mitochondria where they have a good neurological function independent of dopaminergic activity of pramipexole. A neuroprotective effect can be imparted by the ability to exert such an effect. In particular, the document proposes the composition as a therapeutically effective amount of pramipexole of about 0.0625 mg to about 6 mg in combination with a neuroprotective agent and up to 5000 mg of dexpramipexol. However, this document emphasizes the deleterious effects of pramipexole by dopaminergic effects and appears to have been confirmed by the same applicant in WO2008/113003 at about the same time, the entire content of which is incorporated herein by reference. , Tend to support low doses of pramipexole.

According to US Patent Application Publication No. 2013/0116292, which is incorporated herein by reference in its entirety, dexpramipexole, or pharmaceutically acceptable salts and solvates thereof, slows the progression of neuronal cell degeneration. By acting and/or by preventing neuronal cell death. However, there are no further references in the literature to this potentially remarkable effect of dexpramipexole.

The synthesis of dexpramipexol, and its pharmaceutically acceptable salts, particularly dexpramipexol dihydrochloride monohydrate, is described in US Patent Application Publication No. 2012/0253047, the entire contents of which are incorporated herein by reference. It is described in.

Despite the vast body of existing literature, pramipexole still exerts only modest effects in the treatment of Parkinson's disease.

Therefore, the problem of achieving safe and long-term effective treatment of patients with synucleinopathies with pramipexole remains unsolved.

The present invention safely achieves the full efficacy of pramipexole when extended also with a therapeutic window of pramipexole when given neuroprotective intent, delaying its onset in patients with PD-like disorders, and/or Or it derives from the idea that the progression of symptoms can be delayed to a clinically significant extent.

The present invention safely achieves sufficient efficacy of pramipexole by increasing tolerable doses of pramipexole to unexpected levels, delaying onset and/or clinically in patients with PD-like disorders. It shows that the progression of symptoms can be delayed to a significant degree.

It is now known that pharmaceutical preparations such as aprepitant, netupitant, and lorapitant achieve the synucleinopathy-modifying ability of pramipexole by reducing or suppressing the GI side effects of high-dose pramipexole, especially nausea and vomiting. ..

Use of an NK1 receptor antagonist (also referred to as an NK1 receptor inhibitor or simply NK1 antagonist) in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, and therapeutically effective pramipexole or a pharmaceutic drug thereof. It has also been found that it is possible to treat patients suffering from synucleinopathies by maintaining daily doses of pharmaceutically acceptable salts or solvates with minimal adverse effects.

Furthermore, the NK1 antagonist may be higher than the maximum daily dose of pramipexole recommended for the alleviation of motor symptoms of Parkinson's (S)-enantiomeric dose, and even higher (S). )-It has been found to allow safe administration of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine by daily doses including enantiomeric doses. .. As a result, improvement of the pathology of patients with synucleinopathies, especially PD, Lewy body disease, Parkinson's disease associated with glucocerebrosidase (GBA) mutations, and MSA is achieved.

NK1-antagonist as component (a), eg aprepitant, lorapitant, or netupitant, and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2 as component (b) The combination with amines acts to normalize the abnormal ratio of monomeric and oligomeric synuclein species in plasma exosomes from the CNS of patients with synucleinopathies.

Therefore, the present invention, in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, is for the treatment of synucleinopathies in patients in need of such treatment. Provided are NK1 antagonists for use. The combination acts to tend to normalize the abnormal ratio of monomeric and oligomeric synuclein species in CNS-derived plasma exosomes.

The present invention is also a method of treating a patient suffering from synucleinopathies in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine. Also provided is a method comprising treating the patient with an effective amount of a NK1 antagonist.

According to one embodiment, the NK1 antagonist and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine are each mixed with a pharmaceutical carrier to form a pharmaceutical composition. And are separately administered to patients in need of treatment with the combination.

According to another embodiment, said NK1 antagonist and said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine are mixed together and together with a pharmaceutical carrier. It is mixed and formulated into a pharmaceutical composition (fixed-dose combination drug) and administered to a patient in need of such treatment.

All NK1 antagonists that are effective in preventing nausea and vomiting include 6-propylamino-4,5,6,7, including the (S)-enantiomeric doses currently commonly used to treat PD. It can be used in combination with a dose of tetrahydro-1,3-benzothiazol-2-amine, or a higher dose, or even a much higher dose. A number of suitable NK1 antagonists have been disclosed in the literature. The long-term use of this combination is to simultaneously reduce or eliminate the adverse effects induced by the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine alone. Improve the symptoms of synucleinopathies.

As stated in the definition, 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine represents the active ingredient itself, and is derived from a salt or solvate of said active ingredient. It is independent. Similarly, the expressions "salt or solvate" and "salt and solvate" refer to any of the cited NK1 antagonists or 6-propylamino-4,5,6,7-tetrahydro-. With respect to 1,3-benzothiazol-2-amine, salts of any of the above cited NK1 antagonists or the above 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2- It is shown that the amine salt can be solvated with a solvent, usually water.

According to the invention, preferably the NK1 antagonists used are those approved for the prevention of nausea and vomiting after cancer chemotherapy. Indeed, surprisingly, an NK1 receptor inhibitor known to block nausea, vomiting, and diarrhea induced by chemotherapeutic agents affects its efficacy in the treatment of said synucleinopathies. Without blocking the gastrointestinal side effects of the (S)-enantiomer contained in the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine. ing.

Both NK1 antagonists and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine have been used for over 10 years due to their unique efficacy. This finding is surprising, as there are two product families, but no one had considered combining them for the treatment of synucleinopathies. In particular, so far, combining an effective amount of an NK1 antagonist with an anti-synucleinopathy effective amount of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine No one has suggested that this could allow to safely ameliorate the condition of patients suffering from synucleinopathies. Moreover, in the case of pramipexole, such a combination generally allows for administration of the maximum recommended daily dose of pramipexole, and in some cases even for increased doses of pramipexole dihydrochloride monohydrate. No one thought that.

More specifically, in the case of pramipexole dihydrochloride monohydrate, the combination with NK1 antagonists is the maximum recommendation for pramipexole dihydrochloride monohydrate for treating motor symptoms of PD in many patients. Synucleinoides, such as PD, including administration of anti-synucleinopathic therapeutically effective doses well above the dose (4.5 mg/day), thus unexpectedly substantially delaying disease progression It has been found to increase its effectiveness in treating patients suffering from patchy.

Accordingly, the present invention provides a method of treating synucleinopathies, wherein a patient in need of such treatment is treated with an effective daily dose of an NK1 antagonist and an effective daily dose of 6-propylamino-4,5. , 6,7-Tetrahydro-1,3-benzothiazol-2-amine in combination therewith is provided.

Also included in the present invention are pharmaceutically acceptable salts of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine.

According to one embodiment, the present invention generally provides a daily dose that is at least comparable to the approved dose for the prevention or treatment of post-operative nausea and vomiting or the prevention of chemotherapy-induced nausea and vomiting. , And 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine in effective daily doses in combination with a NK1 antagonist.

More specifically, according to this embodiment, said 6-propylamino-4,5,6,7-tetrahydro-1 for use in the treatment of synucleinopathies in a patient in need thereof. , 3-benzothiazol-2-amine is pramipexole or a pharmaceutically acceptable salt or solvate thereof, administered in a daily dose equivalent to 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate. It

According to another embodiment, the present invention provides 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole in pharmaceutical composition component (b) mixed with a pharmaceutical carrier or vehicle. Provided is an NK1 antagonist in a pharmaceutical composition component (a), which comprises, as an active ingredient, an NK1 antagonist mixed with a pharmaceutical carrier or vehicle, which is administered in combination with a 2-amine.

The amount of NK1 antagonist/unit form in the composition is 1 μg to 600 mg, usually 1 mg to 600 mg, and 6-propylamino-4,5,6,7-tetrahydro-1,3-in the composition. The amount of benzothiazol-2-amine/unit form is 0.125 mg to 3000 mg.

According to this embodiment, said NK1 antagonist is preferably admixed with a pharmaceutical carrier for use in the prevention or cure of the adverse effects of pramipexole, for the prevention or treatment of postoperative nausea and vomiting or chemistry. In the treatment of synucleinopathies, pramipexole is present in the composition in an amount per unit form at least comparable to the dose per unit form approved for the prevention of therapy-induced nausea and vomiting. Administration in a pharmaceutical composition comprising pramipexole or a pharmaceutically acceptable salt thereof in an amount per unit form corresponding to 0.125 mg to 45 mg dihydrochloride monohydrate, preferably 0.125 mg to 40-42 mg. To be done.

According to another aspect of this embodiment, the invention provides
(A) at least as much as a dose/unit form approved for the prevention or treatment of post-operative nausea and vomiting or for the prevention of chemotherapy-induced nausea and vomiting, mixed with a pharmaceutical carrier or vehicle. An NK1 antagonist in a pharmaceutical composition comprising the NK1 antagonist as an active ingredient in an amount;
(B) at least the same amount per unit form as the dose/unit form approved for the treatment of Parkinson's disease, in admixture with a pharmaceutical carrier or vehicle, as the active ingredient the pramipexole dihydrochloride monohydrate. A pharmaceutical combination comprising pramipexole dihydrochloride monohydrate in a pharmaceutical composition comprising:

In the combination, component (a) is present in the composition in an amount of 1 μg to 600 mg, usually 1 mg to 600 mg or 1 mg to 300 mg, and component (b) is 0 as pramipexole dihydrochloride monohydrate. .125 mg to 45 mg, preferably 0.125 mg to 40-42 mg, usually 0.125 mg to 20-21 mg.

According to a further embodiment, the invention provides 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt thereof in the treatment of synucleinopathies. For the prevention or treatment of postoperative nausea and vomiting or for the prevention of chemotherapy-induced nausea and vomiting, in combination with a pharmaceutical carrier to prevent or cure the adverse effects of salts and/or solvates. The use of an NK1 antagonist for the preparation of a medicament comprising a pharmaceutical composition comprising, as an active ingredient, said NK1 antagonist in an amount at least as much as the dosage approved in US Pat.

As noted above, the amount of NK1 antagonist per dosage unit form is at least as high as the dose approved for the prevention or treatment of postoperative nausea and vomiting or the prevention of chemotherapy-induced nausea and vomiting. And may be up to 6 times the dose or more, and the amount/unit form of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is 0. It is 125 mg to 3000 mg.

According to yet another embodiment, the present invention provides a pharmaceutical composition comprising an effective amount of a NK1 antagonist per unit form as component (a) in admixture with a pharmaceutical carrier or vehicle, and component (b). A fixed-fixed-dose combination comprising an effective amount of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine per unit form as ..

The amount of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine per IR unit form was safe (when combined with NK1 antagonists) and tolerated. Depending on pramipexole dihydrochloride monohydrate ranging from 0.125 mg to 1500 mg.

Generally, when the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine in the IR formulation is pramipexole dihydrochloride monohydrate, the dose range is ( 0.125 mg to 30 mg, preferably 0.125 mg to 22.5 mg, usually 0.125 mg to 20 mg or 0.125 mg per unit form, depending on its safety and tolerability (when combined with an NK1 antagonist). It is 10 mg.

Dosage of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine in ER formulations, including slow-release compositions and transdermal therapeutic systems, such as transdermal patches The unit form will range from 1.5 mg to 3000 mg, depending on tolerability (when combined with the NK1 antagonist). Generally, when the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate, the dose range/unit form is 1. It will be 5 mg to 45 mg, preferably 1.5 mg to 40-42 mg, or 3 mg to 40-42 mg, usually 3 mg to 20-21 mg.

The dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine as (R)/(S)-mixture was (when combined with an NK1 antagonist) Depending on safety and tolerability, it will range from 50 mg to 1500 mg per IR unit form. The above range includes 0.125 mg to 10 mg (S)-enantiomer amount per IR unit form. If higher doses of pramipexole are administered, the above range will be from 0.125 mg to 22.5 mg, usually 0.125 mg to 20 mg, advantageously 6.5 mg to 20 mg per IR unit form.

Generally, when the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate, the dose range is (NK1 antagonist and Depending on the safety and tolerability (in combination), it is 0.125 mg to 10 mg, preferably 1.5 mg to 10 mg or 6.5 mg to 10 mg per IR unit form. When pramipexole is administered at a higher dose, the dose range will be 0.125 mg to 20 mg, usually 6.5 mg to 20 mg.

Dosage of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine in ER formulations, including slow-release compositions and transdermal therapeutic systems, such as transdermal patches The unit form will range from 3 mg to 3000 mg, depending on tolerability (when combined with the NK1 antagonist).

6-Propylamino-4,5,6,7-tetrahydro-1 as (R)/(S)-mixture in ER formulations, including slow-release compositions and transdermal therapeutic systems, such as transdermal patches The dose/unit form of 3,3-benzothiazol-2-amine is 150 mg to 3000 mg pramipexole dihydrochloride monohydrate, usually 300 mg to 3000 mg, depending on tolerability (when combined with the NK1 antagonist). Range, pramipexole dihydrochloride monohydrate 0.375 mg to 45 mg, usually 0.375 mg to 40-42 mg, or more than 6 mg to 40-42 mg, preferably 0.375 mg to 40-42 mg, or more than 6 mg to 40 Includes (S)-enantiomer dose/unit form corresponding to -42 mg.

Usually, when the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate, the dose range/ER unit form is 3 mg. ~45 mg. Advantageously, when said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is pramipexole or a pharmaceutically acceptable salt thereof, said dose range/ER The unit form is pramipexole dihydrochloride monohydrate greater than 4.5 mg to greater than 45 mg or greater than 6 mg to 45 mg, preferably greater than 4.5 mg to 40-42 mg or greater than 6 mg to 40-42 mg, and in some cases greater than 4.5 mg. ~22.5 mg, preferably more than 6 mg to 20 mg or 6.5 mg to 20 mg. Preferably, the dose range/ER unit form is pramipexole dihydrochloride monohydrate greater than 4.5 mg to 40-42 mg or greater than 6 mg to 40-42 mg, optionally greater than 4.5 mg to 20 mg, preferably 6 mg. This corresponds to over -20 mg or 6.5 mg-20 mg.

When the NK1 antagonist is aprepitant, the aprepitant will provide an IR dose in the range of 10 mg to 250 mg, or in some embodiments 10 mg to 125 mg.

When the NK1 antagonist is fosaprepitant or a pharmaceutically acceptable salt or solvate thereof, the NK1 antagonist will have an IR dose corresponding to 10 mg to 250 mg of aprepitant.

When the NK1 antagonist is lorapitant, the dose per unit form in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is , IR formulation in the range of 15 mg to 270 mg.

Usually, in the method (or use) for the treatment of synucleinopathies according to the invention (in combination with an NK1 antagonist), 6-propylamino, usually contained in a pharmaceutical composition mixed with a pharmaceutical carrier or vehicle. -4,5,6,7-Tetrahydro-1,3-benzothiazol-2-amine is administered to patients in need of such treatment at a daily dose of 1.5 mg to 3000 mg. In practice, the daily dose is
A daily dose of pramipexole dihydrochloride monohydrate corresponding to 1.5 mg to 45 mg of pramipexole or a pharmaceutically acceptable salt thereof;
-Racemic compound or a pharmaceutically acceptable salt thereof in a daily dose of 3 mg to 90 mg of pramipexole dihydrochloride monohydrate (hence clearly corresponding to 1.5 mg to 45 mg of pramipexole dihydrochloride monohydrate). Daily dose of (S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, and pramipexole dihydrochloride monohydrate 1.5 mg to 45 mg (R)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine in a daily dose); and-pramipexole dihydrochloride monohydrate (R)/(S)-mixture in a daily dose of 150 mg to 3000 mg, containing a daily dose of (S)-enantiomer corresponding to 1.5 mg to 45 mg, preferably 1.5 mg to 40-42 mg. (Thus, obviously, the daily dose corresponds to a dose of (S)-enantiomer corresponding to 1.5 mg to 45 mg of pramipexole dihydrochloride monohydrate, preferably 1.5 mg to 40-42 mg, and pramipexole. (R)-6-Propylamino-4,5,6,7-tetrahydro corresponding to 150 mg-3000 mg (1.5 mg-45 mg, preferably 1.5-40-42 mg subtracted) of dihydrochloride monohydrate. Composed of -1,3-benzothiazol-2-amine dose)
Is selected from the group consisting of

In a method (or use) for the treatment of synucleinopathies according to the invention, 6-as an (R)/(S)-mixture, usually contained in a pharmaceutical composition mixed with a pharmaceutical carrier or vehicle. Propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is preferably a pramipexole diamine, including a daily dose of (S)-enantiomer corresponding to 0.375 mg to 45 mg. Includes a daily dose of (S)-enantiomer of hydrochloride monohydrate 6 mg to 45 mg or 6.5 mg to 45 mg, more preferably pramipexole dihydrochloride monohydrate 0.375 mg to 40-42 mg, 6 mg. Said treatment is required at a daily dose of 1.5 mg to 3000 mg or 3.0 mg to 3000 mg, including a daily dose of (S)-enantiomer corresponding to >40 to 42 mg or 6.5 to 40 to 42 mg. Will be administered to patients.

According to a particular embodiment, in the method (or use) the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is 1.5 mg to 45 mg, Preferred is pramipexole dihydrochloride monohydrate, which is administered to the patient at a daily dose of 1.5 mg to 40-42 mg, usually 1.5 mg to 20 mg. According to this embodiment, in the method (or use) the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is combined with an NK1 antagonist in the patient. Be administered to.

When the NK1 antagonist is aprepitant or fosaprepitant, the NK1 antagonist is administered to the patient at a daily dose of 10 mg to 250 mg aprepitant, or in some embodiments 10 mg to 125 mg.

When the NK1 antagonist is lorapitant, the lorapitant is administered to the patient at a daily dose of 15 mg to 270 mg.

As summarized above, the present invention provides a NK1 antagonist component (a) and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-, including fixed dose combinations. Provided is a combination of amine component (b) and its use for treating synucleinopathies in a patient. In particular, the invention provides:
-A method of treating a patient suffering from synucleinopathies in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine component (b). A method comprising treating said patient with an effective amount of a NK1 antagonist;
-For use in combination with a 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine component (b) in the treatment of patients suffering from synucleinopathies NK1 antagonist component (a);
-Preparation of a medicament for treating synucleinopathies in a patient in need thereof in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine Using an NK1 antagonist to: and-a NK1 antagonist component (a) and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-in admixture with a pharmaceutical carrier or vehicle. Fixed-dose combination products comprising a pharmaceutical composition in dosage unit form comprising 2-amine component (b), and its use for treating synucleinopathies in patients.

NK1 antagonist component (a)
As mentioned above, any NK1 antagonist known to be used as an antiemetic agent is 6-propylamino-4,5,6,7-tetrahydro-1,3-benzo for the treatment of synucleinopathies. Potentially useful in combination with thiazol-2-amine.

Long-term use of this combination reduces or eliminates the adverse effects induced by pramipexole itself or racemic or pramipexole as the (S)-enantiomer in the (R)/(S)-mixture, thereby increasing high doses. Of pramipexole and thus of higher neuroprotective doses of pramipexole slows the progression of synucleinopathic disorders.

Advantageously, said NK1 antagonist is
An injectable emulsion (Cinvanti®) in a single-dose vial for intravenous use containing a liquid oral formulation (described in US Patent Application Publication No. 2017/0035774) and 130 mg aprepitant in 18 ml emulsion. 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-in US Pat. No. 9,808,465). 3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (aprepitant) (described in US Pat. No. 5,719,147) ), each of which is hereby incorporated by reference in its entirety.
-[3-{[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4-yl ]Methyl}-5-oxo-2H-1,2,4-triazol-1-yl]phosphonic acid (phosprepitant) (e.g. described as meglumine salts in US Pat. No. 5,691,336, di(cyclohexyl)). Amines) salts as described in U.S. Patent Application Publication No. 2016/0355533, each of which is incorporated herein by reference in its entirety);
-(2S,4S)-4-(4-Acetyl-1-piperazinyl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro 2-Methylphenyl)-N-methyl-1-piperidinecarboxamide (casopitant) (described in US Pat. No. 7,294,630, the entire contents of which are incorporated herein by reference);
-(2S)-1-[(3aS,4S,7aS)-4-hydroxy-4-(2-methoxyphenyl)-7,7-diphenyl-1,3,3a,5,6,7a-hexahydroiso Indole-2-yl]-2-(2-methoxyphenyl)propan-1-one (INN: dapitant);
-(2S,3S)-N-(5-tert-Butyl-2-methoxybenzyl)-2-(diphenylmethyl)-1-azabicyclo[2.2.2]octane-3-amine (malopitant) (US Patent No. 5,807,867, WO 2005/082416 and EP3173071, the entire contents of which are incorporated herein by reference);
-(2S,3S)-2-Diphenylmethyl-3-[(5-isopropyl-2-methoxybenzyl)amino]quinuclidine (INN: ezropitant) (Evangelista S (2001). "Ezlopitant. Pfizer"; Current Opinion in Investigative Drugs: Volume 2 (No. 10): pp 143-143, and Drugs: the Investigative Drugs Journal 6 (Vol. 8): 758-72, each of which is herein incorporated by reference in its entirety. Incorporated into));
-(2S)-N-{2-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-[4-(cyclopropylmethyl)piperazin-1-yl]-N-methyl-2-phenyl Acetamide (INN: fipopitant);
-N-[(2R)-1-[acetyl-[(2-methoxyphenyl)methyl]amino]-3-(1H-indol-3-yl)propan-2-yl]-2-(4-piperidine- 1-ylpiperidin-1-yl)acetamide (INN: lanepitant);
-2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinyl ] Propanamide (Netupitant) (described in US Pat. No. 6,297,375, US Pat. No. 6,593,472, US Pat. No. 6,719,996, US Pat. No. 8,951,969). The description of the publication contains 300 mg of netupitant and palonosetron hydrochloride in an oral composition in an amount corresponding to 0.5 mg of palonosetron base, and is referred to hereinbelow as "netupitant-300/palonosetron-0.5". Each of which is incorporated herein by reference in its entirety);
-(2R,4S)-4-[(8aS)-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-N-[ (1R)-1-[[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methylpiperidine-1-carboxamide (INN: orbepitant) ( U.S. Patent Application Publication No. 2005/0176715, and U.S. Patent Application Publication No. 2011/01616650, described as crystalline maleates, each of which is incorporated herein by reference in its entirety);
-(5S,8S)-8-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}methyl)-8-phenyl-1,7-diazaspiro[4.5]decane 2-one (lorapitanto) (described in US Pat. No. 7,049,320, its injectable form is described in US Pat. No. 9,101,615, each of which is incorporated by reference in its entirety). Are incorporated herein);
-3-((3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethylphenyl]ethoxy]-4-(4-fluorophenyl)-1,3 , 3a,4,5,6,7,7a-octahydroisoindol-2-ylcyclopent-2-en-1-one (serlopitant) (US Pat. No. 7,544,815 and US Pat. 217,731, each of which is incorporated herein by reference in its entirety);
-2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl -Amide (INN: vestipitant) (described in WO 2001/25219 and in WO 2012/175434 as an intravenous formulation which is less prone to cause hemolysis, each of which is herein incorporated by reference in its entirety. Incorporated into));
-(2S,3S)-N-[(2-Methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]phenylmethyl]-2-phenylpiperidin-3-amine (INN: vofopitant) (Gardner) CJ et al., Regul Pept. 1996 Aug 27;65(l):45-53, the entire contents of which are incorporated herein by reference).
Is selected from the group consisting of

Examples of pharmaceutically acceptable salts of NK1 antagonists which are basically advantageous include those with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and phosphoric acid. Acid addition salts and formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, gluconic acid Acid addition salts with organic acids such as aspartic acid and glutamic acid.

Illustrative of pharmaceutically acceptable salts of acidic NK1 antagonists, such as fossaprepitant, are salts with inorganic bases, such as alkali metal or alkaline earth metal salts, and their entire contents by reference. Salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine (meglumine) salts, and salts with amino acids, as described in US Pat. No. 5,691,336, which are incorporated herein by reference.

Advantageous NK1 antagonists used in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine are:
-Aprepitant and pharmaceutically acceptable salts and solvates thereof,
-Fosaprepitant and pharmaceutically acceptable salts and solvates thereof,
-Casopitant and pharmaceutically acceptable salts and solvates thereof,
-Malopitant and pharmaceutically acceptable salts and solvates thereof,
-Ediopitant and its pharmaceutically acceptable salts and solvates,
-Ranepitant and pharmaceutically acceptable salts and solvates thereof,
-Netupitant and pharmaceutically acceptable salts and solvates thereof,
-Orvapitant and its pharmaceutically acceptable salts and solvates,
-Lorapitant and pharmaceutically acceptable salts and solvates thereof,
-Serlopitant and its pharmaceutically acceptable salts and solvates,
-Vestipitant and pharmaceutically acceptable salts and solvates thereof,
-Vofofitant and its pharmaceutically acceptable salts and solvates,
-Netupitant-300/Palonosetron-0.5
Is selected from the group consisting of

Aprepitant, fosaprepitant meglumine, fosaprepitant di(cyclohexylamine), lorapitant, lorapitant hydrochloride, and netupitant-300/palonosetron-0.5 are particularly advantageous NK1 antagonists.

In accordance with the present invention, NK1 receptor antagonists approved for the prevention or treatment of postoperative nausea and vomiting or for the prevention of chemotherapy-induced nausea and vomiting are particularly useful. Commercially available aprepitant (Emend®) in capsules containing 40 mg, 80 mg, or 125 mg of aprepitant; commercial fosaprepitant meglumine (Emend®) in vials containing 115 mg or 150 mg of fossaprepitant Injection); lorapitant (Varubi®) provided in 90 mg tablets; provided in a fixed dose combination of 300 mg netupitant and 0.5 mg capsules containing the NK1 antagonist palonosetron (as the hydrochloride salt) Netupitant-300/palonosetron-0.5 (Akynzeo®) is the preferred NK1 antagonist.

In the methods, uses, and combinations comprising fixed dose combination as described above, the NK1 antagonist is present in an amount per unit form and is administered at a daily dose of 1 μg to 600 mg, usually 1 mg to 600 mg, or 1 mg to 300 mg. It

More specifically, in said combination, said NK1 antagonist is a daily dose of aprepitant corresponding to aprepitant 10 mg to 250 mg and its pharmaceutically acceptable salts and solvates; aprepitant equivalent to 10 mg to 250 mg 1 Daily dose of fossaprepitant and pharmaceutically acceptable salts and solvates thereof; Lorapitant corresponding to 15 mg to 270 mg of lorapitant and pharmaceutically acceptable salts and solvates thereof, equivalent to 300 mg to 600 mg Daily dose of Netupitant and pharmaceutically acceptable salts and solvates thereof; and Netupitant-300/Palonosetron-0.5.

When administered to a patient suffering from synucleinopathies in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, the NK1 antagonist Each is formulated into a pharmaceutical composition in the form of a dosage unit containing the NK1 antagonist as an active ingredient in admixture with a pharmaceutical carrier or vehicle.

In particular, said NK1 antagonist active ingredient of said pharmaceutical composition corresponds to an amount of aprepitant and a pharmaceutically acceptable salt and solvate thereof per unit form corresponding to 10 mg to 250 mg of aprepitant; 10 mg to 250 mg of aprepitant. An amount per unit form of fossaprepitant and pharmaceutically acceptable salts and solvates thereof; An amount per unit form of lorapitant equivalent to 15 mg to 270 mg of lorapitant and pharmaceutically acceptable salts and solvates thereof; An amount per unit form corresponding to 300 mg to 600 mg of netupitant and its pharmaceutically acceptable salts and solvates; and Netupitant-300/palonosetron-0.5.

Advantageously, said NK1 antagonist is aprepitant in an amount of 10 mg to 250 mg per unit form; an amount of fosaprepitant meglumine per unit form corresponding to 10 mg to 250 mg of aprepitant; or 15 mg to 270 mg or 30 mg to 270 mg of unit form. It is the amount of lorapitant.

As described above, the NK1 antagonist is used in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, and therapeutically effective pramipexole or a pharmaceutically acceptable salt thereof while minimizing adverse effects. By maintaining a daily dose of salt or solvate, it is possible to treat patients suffering from synucleinopathies.

Therefore, in order to ensure a reliable and safe co-administration of the NK1 antagonist and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, the present invention provides: A pharmaceutical composition in a dosage unit form comprising an effective amount per unit form of said NK1-antagonist, and an effective amount per unit form of said 6-propylamino-4,5,6,7 mixed with a pharmaceutical carrier or vehicle. -Provides a fixed dose combination consisting of tetrahydro-1,3-benzothiazol-2-amine.

These NK1 antagonist/6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine fixed dose combinations are shown in the "Pharmaceutical Compositions" section below. ing.

6-Propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine component (b)
As described in the definitions above, 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is
-Pramipexole, ie (S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, and pharmaceutically acceptable salts and solvates thereof;
-Racemic compound, i.e. (R,S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, and pharmaceutically acceptable salts and solvates thereof And-a pharmaceutical composition containing a therapeutically effective amount of the (S)-enantiomer, usually in admixture with a pharmaceutical carrier or vehicle (e.g., U.S. Patent Application Publication No. (R)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-in the pharmaceutical composition according to 2008/0014259). It is selected from the group consisting of a mixture of 2-amine and (S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine.

Examples of pharmaceutically acceptable salts or solvates of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine include inorganic or organic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, acetic acid, propionic acid, stearic acid, glycolic acid, oxalic acid, succinic acid, lactic acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, tartaric acid, citric acid Acid, ascorbic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfone (isethion) acid, p-toluenesulfonic acid, 2-naphthalenesulfonic acid , 4-aminobenzenesulfon (sulfanyl) acid, 2,6-naphthalenedisulfonic acid, 1,5-naphthalenedisulfonic acid, and pamo (embonic) acid. The solvating solvent is usually water.

In the case of pramipexole or a pharmaceutically acceptable salt or solvate thereof, the commercially available pramipexole dihydrochloride monohydrate is preferably 6-propylamino-4,5,6,7-tetrahydro-1,3. -Benzothiazol-2-amine. For example, a stable pharmaceutical composition comprising pramipexole dihydrochloride monohydrate, as disclosed in WO2012/0140604 and WO2008/122638, each of which is incorporated herein by reference in its entirety, and its entire content by reference. The sustained release compositions comprising pramipexole dihydrochloride monohydrate disclosed in US Pat. No. 8,399,016, incorporated herein by reference, are NK1 antagonists for the treatment of synucleinopathies. May be useful for use in combination with.

Racemic and pramipexole, described in US Pat. No. 4,886,812, which is incorporated herein by reference in its entirety, are each useful for the treatment of synucleinopathies in combination with NK1 antagonists. It is 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine.

(S)/(R)-mixtures, i.e. therapeutically effective amounts of (R)-6-propylamino-4,5,6,7-tetrahydro-, as described in U.S. Patent Application Publication No. 2008/0014259. 1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt and solvate thereof and a therapeutically effective amount of (S)-6-propylamino-4,5,6,7-tetrahydro-1,3 Pharmaceutical compositions comprising benzothiazol-2-amine or pharmaceutically acceptable salts and solvates thereof are also useful for the treatment of synucleinopathies in combination with NK1 antagonists 6-propylamino-4,5. , 6,7-Tetrahydro-1,3-benzothiazol-2-amine.

For the treatment of synucleinopathies, 6-propylamino-4,5,6,7-tetrahydro-1,3-, in combination with the NK1 antagonist described in the section "NK1 antagonist component (a)" above. Benzothiazol-2-amine, in admixture with a pharmaceutical carrier or vehicle, in an amount corresponding to 0.125 mg to 3000 mg of pramipexole dihydrochloride monohydrate, said 6-propylamino-4,5,6,7. -Formed into a pharmaceutical composition comprising tetrahydro-1,3-benzothiazol-2-amine. The composition is administered to a patient in need thereof in a daily dose of 0.375 mg to 3000 mg in combination with a daily dose of NK1 antagonist of 1 μg to 600 mg, usually 1 mg to 600 mg.

According to the invention, 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is preferably
A dose of (S)-6-propylamino-4,5,6,7 per unit form corresponding to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate, preferably 0.125 mg to 40-42 mg. -Tetrahydro-1,3-benzothiazol-2-amine (INN: pramipexole) and its pharmaceutically acceptable salts and solvates, especially its dihydrochloride monohydrate (USAN: pramipexole hydrochloride);
A dose per unit form corresponding to 0.25 mg to 90 mg of pramipexole dihydrochloride monohydrate (R,S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzo Thiazol-2-amine (racemic) and its pharmaceutically acceptable salts and solvates (hence obviously pramipexole dihydrochloride monohydrate up to 0.125 mg to 45 mg, preferably 0.125 mg to 40 mg). -Smg of (S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine corresponding to -42 mg and pramipexole dihydrochloride monohydrate A dose per unit form corresponding to 0.125 mg to 45 mg, preferably 0.125 mg to 40 mg of (R)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2- Amine), and preferably, pramipexole dihydrochloride monohydrate 0.25 mg to 90 mg, preferably 0.25 mg to 80-84 mg (thus clearly pramipexole dihydrochloride monohydrate 0.125 mg A dose of (S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine corresponding to ~40-42 mg and pramipexole dihydrochloride monohydrate A dosage form of (R)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine corresponding to a dose of 0.125 mg to 40-42 mg. ); and -(R)/(S)-mixture, ie 6-propylamino-4, at a dose per unit form corresponding to 50 mg to 3000 mg of pramipexole dihydrochloride monohydrate, preferably 150 mg to 3000 mg. A pharmaceutical composition in the form of a dosage unit comprising 5,6,7-tetrahydro-1,3-benzothiazol-2-amine, wherein the amount per unit form is pramipexole dihydrate monohydrate. It contains a (S)-enantiomer amount corresponding to 125 mg to 45 mg, preferably 0.125 mg to 45 mg (hence, apparently, the amount per unit form is from pramipexole dihydrochloride monohydrate 0.125 mg to (S)-enantiomer in an amount corresponding to 45 mg, preferably 0.125 mg to 40-42 mg, and 50 mg pramipexole dihydrochloride monohydrate, preferably 150 mg to 3000 mg (0.125 mg to 45 (R)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-, in an amount per unit form corresponding to 1 mg (usually subtracting 0.125-40-42 mg) (Comprised of amines), and preferably containing an amount of (S)-enantiomer corresponding to 0.125 mg to 40-42 mg of pramipexole dihydrochloride monohydrate (hence obviously the amount per unit form). Is (S)-enantiomer in an amount corresponding to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate, preferably 0.125 mg to 40-42 mg, and 50 mg of pramipexole dihydrochloride monohydrate, preferably Is (R)-6-propylamino-4,5,6,7-tetrahydro in an amount per unit form corresponding to 150 mg to 3000 mg (0.125 mg to 45 mg, preferably 0.125 to 40-42 mg is subtracted). -1,3-benzothiazol-2-amine), and a composition.

As indicated in the definitions, an effective daily dose of pramipexole or the (S)-enantiomer is at least a dose equivalent to the approved daily dose of pramipexole dihydrochloride monohydrate for the treatment of PD. is there. The above approved daily dose is 0.375 mg to 4.5 mg. However, in accordance with the present invention, the combination of an NK1 antagonist with said pramipexole or (S) enantiomer results in the administration of an approved daily dose of pramipexole dihydrochloride monohydrate for the treatment of Parkinson's disease. It is specified herein that it is possible without adverse effects, but also allows the administration of pramipexole dihydrochloride monohydrate daily doses above and above the approved dose. Has been done.

In particular, in the above combination with an NK1 antagonist, pramipexole dihydrochloride monohydrate, depending on tolerability (when combined with an NK1 antagonist), is between 0.375 mg and 45 mg, preferably 0.375 mg. A daily dose of -40-42 mg may be administered to patients suffering from synucleinopathies, including pediatric patients. According to the present invention, the daily dose range of 0.375 mg to 45 mg, preferably 0.375 mg to 40-42 mg includes the low doses administered during the titration period. More specifically, the daily dose range is from 1.5 mg to 45 mg, 1.6 mg to 45 mg, 1.625 mg to 45 mg, 3 mg to 45 mg, more than 4.5 mg to 45 mg, 4.8 to 45 mg, more than 6 mg. It can be selected from the group consisting of 45 mg, and 6.5 mg to 45 mg. Preferably, the daily dose range is from 1.5 mg to 40-42 mg, 1.6 mg to 40-42 mg, 1.625 mg to 40-42 mg depending on tolerability (when combined with a NK1 antagonist). 3 mg to 40-42 mg, more than 4.5 mg to 40-42 mg, 4.8 mg to 40-42 mg, more than 6 mg to 40-42 mg, more than 10 mg to 40-42 mg, 13.5 mg to 40-42 mg, 13.5 mg ˜30 mg, and 13.5 mg to 20-21 mg.

6-Propylamino-4,5,6,7 when administered to a patient suffering from synucleinopathies in combination with the NK1 antagonist described in the section “NK1 antagonist component (a)” above. -Tetrahydro-1,3-benzothiazol-2-amine is mixed with a pharmaceutical carrier or vehicle to give 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole as an active ingredient. It is formulated into a pharmaceutical composition in the form of a dosage unit containing 2-amine.

According to the present invention, the pharmaceutical composition component (b) comprises, as an active ingredient, pramipexole or a pharmaceutically acceptable salt thereof, wherein pramipexole dihydrochloride monohydrate in an IR preparation is 0.125 mg to 30 mg or 20-21 mg, usually in an amount per unit form corresponding to 1.5 mg to 10 mg, or to pramipexole dihydrochloride monohydrate in an ER formulation 1.5 to 45 mg, preferably 1.5 mg to 40-42 mg Included in the amount per unit form.

More specifically, the pramipexole is 0.125 to 45 mg, preferably 1.5 mg to 45 mg, 1.625 mg to 45 mg, 3 mg to 45 mg, more than 4.5 mg to 45 mg, 4.8 mg to 45 mg, more than 6 mg. Present in the composition in an amount per unit form range corresponding to the amount per unit form of pramipexole dihydrochloride monohydrate selected from the group consisting of 45 mg, and >10 mg to 45 mg. .. Particularly, the pramipexole is 0.125 mg to 40-42 mg, 0.125 mg to 30 mg, 0.125 to 20-21 mg, 1.5 mg to 40-42 mg, 1.625 mg to 40-42 mg, 3 mg to 40-42 mg, A unit form of pramipexole dihydrochloride monohydrate selected from the group consisting of greater than 4.5 mg to 40-42 mg, 4.8 mg to 40-42 mg, greater than 6 mg to 40-42 mg, and greater than 10 mg to 40-42 mg. It is present in the composition in an amount range per unit form corresponding to the amount range per unit.

In a preferred embodiment, the invention provides pramipexole dihydrochloride monohydrate 13.5 mg to 45 mg, 13.5 mg to 40-42 mg, 13.5 mg to 30 mg, or 13.5 mg mixed with a pharmaceutical carrier or vehicle. There is provided a pharmaceutical composition in a dosage unit form containing pramipexole and pharmaceutically acceptable salts and solvates thereof as an active ingredient in an amount per unit form corresponding to ˜20-21 mg.

As described above, the NK1 antagonist is used in combination with pramipexole or a pharmaceutically acceptable salt or solvate thereof, and therapeutically effective pramipexole or a pharmaceutically acceptable salt thereof while minimizing adverse effects. By maintaining a daily dose of salt or solvate, it is possible to treat patients suffering from synucleinopathies.

In order to provide the co-administration of the NK1 antagonist and the pramipexole or a pharmaceutically acceptable salt or solvate thereof, the present invention provides a NK1 antagonist as an active ingredient in combination with a pharmaceutical carrier or vehicle. A pharmaceutical composition in a dosage unit form comprising; and a fixed dose combination comprising pramipexole and pharmaceutically acceptable salts and solvates thereof.

A fixed dose combination of NK1-antagonist/6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is shown in the "Pharmaceutical Composition" section below. There is.

Specific Aspects of the Invention According to the first aspect, the present invention results in 6-propylamino-4,5, suffering from synucleinopathies by simultaneously and long-term administration of an NK1 antagonist to the patient. , 6,7-Tetrahydro-1,3-benzothiazol-2-amine. Methods for safely delaying or reversing disease progression in patients treated with.

More specifically, the present invention is a method of treating synucleinopathies in a patient, wherein the patient in need thereof is treated with an effective daily dose of a NK1 antagonist and an effective daily dose of 6 -Propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is provided in combination therewith.

Any of the NK1 antagonists described in the section "NK1 antagonist component (a)" can be used according to the method of this aspect of the invention.

In practicing the methods of this invention, the daily doses of these NK1 antagonists are used to prevent or treat nausea and vomiting in patients undergoing surgery or cancer chemotherapy according to current protocols for such treatment or prevention. At least as much as the daily dose of The daily dose is 1 μg to 600 mg, usually 1 mg to 600 mg, or 1 mg to 300 mg.

NK1 antagonists selected from the group consisting of aprepitant and pharmaceutically acceptable salts and solvates thereof, and lorapitant and pharmaceutically acceptable salts and solvates thereof are particularly advantageous NK1 antagonists. ..

As mentioned above, 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is a racemate, pramipexole, and (R)/(S)-mixtures and their pharmaceuticals. Selected from the group consisting of pharmaceutically acceptable salts and solvates.

The dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine per dosage unit form and the daily dose are the above-mentioned "6-propylamino-4,5,5. 6,7-Tetrahydro-1,3-benzothiazol-2-amine". The dose per unit form of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate, preferably It consists of or comprises an amount per unit form of the (S) isomer, corresponding to more than 6 mg to 45 mg, usually 0.125 mg to 40-42 mg, preferably more than 6 mg to 40-42 mg.

According to one embodiment, 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is
-Pramipexole dihydrochloride monohydrate 0.375 mg-45 mg, preferably more than 6 mg-45 mg or 6.5 mg-45 mg, usually 0.375 mg-40-42 mg, preferably more than 6 mg-40-42 mg or 6.5 mg- (S) in a dose/unit form corresponding to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate, preferably 0.125 mg to 40-42 mg, administered in a daily dose equivalent to 40-42 mg. -6-Propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine (INN: pramipexole) and its pharmaceutically acceptable salts, especially its dihydrochloride monohydrate (USAN: pramipexole hydrochloride);
-Pramipexole dihydrochloride monohydrate 0.375 mg to 45 mg, preferably more than 12 mg to 45 mg or 13 mg to 45 mg, usually 0.375 mg to 40-42 mg, preferably more than 12 mg to 40-42 mg or 13 mg to 40-42 mg. Pramipexole dihydrochloride monohydrate 0.125 mg to 45 mg, preferably more than 12 mg to 45 mg or 13 mg to 45 mg, usually 0.125 mg to 40-42 mg, preferably more than 12 mg to 40, administered at a corresponding daily dose. In a dose/unit form of 0.25 mg to 90 mg, preferably more than 12 mg to 90 mg, usually 0.25 mg to 80 mg, containing an amount per unit form of S-enantiomer corresponding to -42 mg or 13 mg to 40-42 mg. (R,S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine (racemic form) and pharmaceutically acceptable salts thereof; and-pramipexole Dihydrochloride monohydrate 0.375 to 45 mg, preferably more than 6 mg to 45 mg or 6.5 mg to 45 mg, usually 0.375 mg to 40-42 mg, preferably more than 6 mg to 40-42 mg or 6.5 mg to 40- Pramipexole dihydrochloride monohydrate 0 administered at a daily dose of 150 mg to 300 mg, preferably 300 mg to 3000 mg or 450 mg to 3000 mg, including a daily dose of the (S)-enantiomer corresponding to 42 mg. 125-45 mg, preferably more than 6 mg to 45 mg or 6.5 mg to 45 mg, usually 0.125 to 40-42 mg, preferably more than 6 mg to 40-42 mg, or S enantiomer corresponding to 6.5 mg to 40-42 mg. A dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-of 50 mg to 3000 mg, preferably 150 mg to 3000 mg, including the amount per unit form of the body. It is selected from the group consisting of (R)/(S)-mixtures, which is a pharmaceutical composition in dosage unit form containing a 2-amine.

In the method for treating synucleinopathies according to the present invention, the above effective daily dose of NK1 antagonist is usually administered to a patient in need thereof in combination with pramipexole dihydrochloride monohydrate. The pramipexole dihydrochloride monohydrate in a pharmaceutical composition mixed with a pharmaceutical carrier or vehicle is administered to the patient at a daily dose of 0.375 mg to 45 mg, preferably 0.375 mg to 40-42 mg. ..

According to one embodiment,
The NK1 antagonist includes aprepitant and pharmaceutically acceptable salts and solvates thereof, fosaprepitant and pharmaceutically acceptable salts and solvates thereof, lorapitant, and pharmaceutically acceptable salts and solvates thereof. , Netupitant and pharmaceutically acceptable salts and solvates thereof (each daily dose described in the section "NK1 antagonists"), and netupitant-300/palonosetron-0.5 (once daily Or once every 2 to 4 days).
The 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is the same as "6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole. 2-amine component (b)”, the daily dose of pramipexole and pharmaceutically acceptable salts and solvates thereof.

According to an advantageous embodiment, in the method of the invention, the NK1 antagonist is aprepitant, fosaprepitant meglumine, or lorapitant, and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzo Thiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof is the daily dose of pramipexole dihydrochloride monohydrate described in the respective section.

According to a particular embodiment, in the method (or use), said effective daily dose of said NK1 antagonist is administered to said patient in combination with pramipexole dihydrochloride monohydrate. The daily dose of 5 mg to 45 mg, usually 1.5 mg to 45 mg, preferably 1.5 mg to 40-42 mg, usually 1.5 mg to 20-21 mg is administered to the patient.

Preferably, in the method of treating synucleinopathies in a patient according to the invention,
The NK1 antagonist is a daily oral dose of 10 mg to 250 mg of aprepitant; a daily injectable dose of fosuaprepitant meglumine corresponding to aprepitant of 10 mg to 250 mg; Lorapitant; or Netupitant-300/Palonosetron-0.5;
The 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof is 1.5 mg to 45 mg, usually 1. Pramipexole dihydrochloride monohydrate in an effective daily oral dose of 5 mg to 22.5 mg, preferably 1.5 mg to 40-42 mg, usually 1.5 mg to 20-21 mg.

The NK1 antagonist and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine are mixed with a pharmaceutical carrier or vehicle as described below. And may be co-formulated into a pharmaceutical composition.

By the method of the present invention, Parkinson's disease, dementia with Lewy bodies, mutation of glucocerebrosidase gene, multiple system atrophy, Alzheimer's disease, Lewy body variants of Alzheimer's disease, neurodegeneration with brain iron accumulation, and gluco Allows safe treatment of synucleinopathies, such as Parkinson's disease associated with cerebrosidase (GBA) mutations.

According to a second aspect, the present invention provides the treatment of synucleinopathies in a patient in need thereof with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole- Provided are NK1 antagonists for use in combination with 2-amines.

Any of the NK1 antagonists described in the section "NK1 antagonist component (a)" can generally be used in a dosage unit form according to this second aspect of the invention.

In particular, this second aspect of the invention provides for the treatment of synucleinopathies in patients in need of such treatment from 0.375 mg to 3000 mg of 6-propylamino-4,5,6,7- Provided is an amount of NK1 antagonist per unit form of 1 μg to 600 mg, usually 1 mg to 600 mg or 1 mg to 300 mg for use in combination with a daily dose of tetrahydro-1,3-benzothiazol-2-amine.

For use according to the present invention, the daily dose of these NK1 antagonists is the daily dose for preventing or treating nausea and vomiting in patients undergoing surgery or cancer chemotherapy according to current protocols for treatment or prevention. At least about the same as the dose. The daily dose is in the range of 1 μg to 600 mg, usually 1 mg to 600 mg or 1 mg to 300 mg.

For its use for the treatment of synucleinopathies according to the invention, the aforementioned effective daily dose of NK1 antagonists exemplified in the section "NK1 antagonist component (a)" is Propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine component (b)" as described in the section "Effective daily dose of 6-propylamino-4. , 5,6,7-Tetrahydro-1,3-benzothiazol-2-amine in combination with a patient in need of such treatment.

According to one embodiment, the NK1 antagonist is in a daily dose of 50-3000 mg, 150 mg-3000 mg or 300 mg-3000 mg, usually in an amount of 1 μg-600 mg, usually 1 mg-600 mg or 1 mg-300 mg per unit form. And as a (R)/(S)-mixture for use in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine. The daily dose is 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate, preferably more than 6 mg to 45 mg or 6.5 mg to 45 mg, usually 0.375 mg to 40-42 mg, preferably more than 6 mg to 40-42 mg or It contains doses of (S)-enantiomer corresponding to 6.5 mg to 40-42 mg.

The 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate 0.75 mg to 90 mg, preferably more than 12 mg to 90 mg or 13 mg. ˜90 mg, usually 0.75 mg to 80 mg, preferably more than 12 mg to 80 mg or 13 mg to 80 mg may be the racemate, therefore pramipexole dihydrochloride monohydrate 0.75 mg to 40− 42 mg, preferably greater than 12 mg to 40-42 mg or 13 mg to 40-42 mg, 0.75 mg to 40-42 mg, preferably greater than 12 mg to 40-42 mg or 13 mg to 40-42 mg of the (S)-enantiomer It may deliver a daily dose.

Preferably, pramipexole dihydrochloride monohydrate 1.5 mg to 45 mg, advantageously more than 4.5 mg to 45 mg, more advantageously to 4.8 mg to 45 mg, preferably more than 6 mg to 45 mg or 6.5 mg to 45 mg. , Usually 1.5 mg to 40-42 mg, advantageously more than 4.5 mg to 40-42 mg, more advantageously 4.8 mg to 40-42 mg, preferably more than 6 mg to 40-42 mg or 6.5 mg to 40-42 mg. The daily dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine corresponding to pramipexole or a pharmaceutically acceptable salt or solvate thereof is Is.

For the treatment of synucleinopathies, the NK1 antagonist and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, respectively, in admixture with a pharmaceutical carrier or vehicle. , NK1 antagonist and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, respectively, to prepare a pharmaceutical composition in a dosage unit form.

Generally, the NK1 antagonist and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine are
Each mixed with a pharmaceutical carrier or vehicle,
An amount of said NK1 antagonist per unit form of 1 μg to 600 mg;
A pharmaceutical composition in the form of a dosage unit, each containing said amount of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine in an amount of 0.125 mg to 3000 mg per unit. Each is formulated.

In particular, according to this second aspect, the invention provides a combination drug comprising:
Ingredient (a): A pharmaceutical composition in dosage unit form, containing as an active ingredient 1 μg to 600 mg, usually 1 mg to 600 mg or 1 mg to 300 mg, of said NK1 antagonist in admixture with a pharmaceutical carrier or vehicle. NK1 antagonist in; and component (b): 0.375 mg to 45 mg of pramipexole dihydrochloride monohydrate for use in the treatment of synucleinopathies in patients in need thereof, preferably 0. A daily dose equivalent to 375 mg to 40-42 mg of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzo selected from the group consisting of pramipexole and its pharmaceutically acceptable salts. Thiazol-2-amine.

Preferably, the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is likewise greater than 4.5 mg to 45 mg, greater than 6 mg to 45 mg or 6.5 mg. Pramipexole dihydrochloride monohydrate in a pharmaceutical composition in a dosage unit form in an amount of 45 mg, preferably more than 4.5 mg to 40-42 mg, more than 6 mg to 40-42 mg or 6.5 mg to 40-42 mg. It is a thing.

Advantageously, said NK1 antagonist component (a) is aprepitant and its pharmaceutically acceptable salts and solvates, fosaprepitant and its pharmaceutically acceptable salts and solvates, lorapitant and its pharmaceutically Acceptable salts and solvates, netupitant and pharmaceutically acceptable salts and solvates thereof (amounts per unit form shown in the section "NK1 antagonist component (a)", respectively); It is selected from the group consisting of Netupitant-300/Palonosetron-0.5.

Preferably, the NK1 antagonist is a daily oral dose of aprepitant of 10 mg to 250 mg; an effective daily injectable dose of fosuaprepitant meglumine equivalent to aprepitant of 10 mg to 250 mg; an effective daily equivalent of 15 mg to 270 mg or 30 mg to 270 mg. Oral dose of lorapitant; or netupitant-300/palonosetron-0.5.

The use according to the invention is carried out under the conditions indicated herein above for carrying out the method of treatment.

According to this second aspect, the invention also provides
A combination drug comprising (a) an NK1 antagonist; and (b) 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine useful for the treatment of synucleinopathies provide.

For this purpose any of the NK1 antagonists indicated in the section “NK1 antagonist component (a)” can be used according to the method of this aspect of the invention.

Usually, the NK1 antagonist component (a) is used at a dose at least comparable to the approved dose for the prevention or treatment of postoperative nausea and vomiting, or for the prevention of chemotherapy-induced nausea and vomiting. , 6-Propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine component (b) is used according to conventional protocols for the treatment of synucleinopathies such as PD. It

The amount and daily dose of the NK1 antagonist and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine per unit form can be determined according to the first aspect of the invention and the present invention. It is as described above in this second aspect of the specification.

According to a third aspect, the invention requires such treatment in combination with an effective daily dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine. Use of an NK1 antagonist for the preparation of a medicament for treating synucleinopathies in a patient.

For this use, the NK1 antagonist is mixed with a pharmaceutical carrier or vehicle and formulated into a pharmaceutical composition containing the NK1 antagonist as an active ingredient, and synucleino in a patient in need of such treatment. It is administered simultaneously or sequentially in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine for the treatment of pathies.

In the pharmaceutical composition, the NK1 antagonist is mixed with a pharmaceutical carrier and is in unit form for oral, intravenous, transdermal, and/or transdermal administration, as described below. Formulated.

Any of the NK1 antagonists described in the section "NK1 antagonist component (a)" is according to this third aspect of the invention "6-propylamino-4,5,6,7-tetrahydro-1, Synuclei in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine as described in section "3-Benzothiazol-2-amine component (b)". It can be used as an active ingredient of a pharmaceutical composition indicated as a drug for the treatment of nopathies.

According to an embodiment of this third aspect, said medicament is effective in admixture with a pharmaceutical carrier or vehicle in an amount of 1 μg to 600 mg, usually 1 mg to 600 mg or 1 mg to 300 mg per unit form of said NK1 antagonist. A pharmaceutical composition in the form of a dosage unit, which comprises as an ingredient. This drug was used in patients with synucleinopathies in combination with a daily dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine Provided for administration at a daily dose of 0.375 mg to 3000 mg with a (S)-enantiomer amount of 0.375 mg to 45 mg, preferably 0.375 mg to 40-42 mg.

These daily doses of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine include low pramipexole daily doses useful for administration during the escalation period. .. At the end of the titration period, the drug thus produced was treated with a daily dose of pramipexole not previously achieved (without combination with NK1 antagonists), as shown in the component (b) section. Allows for safe intake.

In particular, the NK1 antagonist active ingredient is aprepitant in an amount per unit form corresponding to 10 mg to 250 mg aprepitant and pharmaceutically acceptable salts and solvates thereof; an amount per unit form corresponding to 10 mg to 250 aprepitant. And a pharmaceutically acceptable salt and solvate thereof; an amount of lorapitant equivalent to 15 mg to 270 mg lorapitant and a pharmaceutically acceptable salt and solvate thereof; equivalent to 300 mg to 600 mg Per unit form of Netupitant and pharmaceutically acceptable salts and solvates thereof; and Netupitant-300/palonosetron-0.5.

Advantageously, said NK1 antagonist corresponds to an amount of aprepitant of 10 mg to 250 mg per unit form; an amount of fospreprepitant meglumine corresponding to 10 mg to 250 mg of aprepitant; or 15 mg to 270 mg or 30 mg to 270 mg. The amount of lorapitant per unit form.

In combination with the advantageous NK1 antagonist in the pharmaceutical composition, the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is pramipexole or a pharmaceutical composition thereof. Acceptable salt, pramipexole dihydrochloride monohydrate 0.375 mg to 45 mg, advantageously more than 4.5 mg to 45 mg, preferably more than 6 mg to 45 mg, or 6.5 mg to 45 mg, or if Depending on, 1.5 mg to 22.5 mg, 1.6 mg to 22.5 mg, 1.625 mg to 22.5 mg, 3 mg to 22.5 mg, more than 4.5 mg to 22.5 mg, 4.8 mg to 22.5 mg, It can be safely administered to patients suffering from synucleinopathies in daily doses corresponding to >6 mg to 22.5 mg or 6.5 mg to 22.5 mg. Generally, the daily dose will be 0.375 mg to 40-42 mg of pramipexole dihydrochloride monohydrate, advantageously greater than 4.5 mg to 40-42 mg, preferably greater than 6 mg to 40-42 mg or 6.5 mg-40. -42 mg, or, in some cases, 1.5 mg to 20-21 mg, 1.6 mg to 20-21 mg, 1.625 mg to 20-21 mg, 3 mg to 20-21 mg, more than 4.5 mg to 20-21 mg, 4.8 mg. ~20-21 mg, more than 6 mg to 20-21 mg or 6.5 mg to 20-21 mg.

Said preferred NK1 antagonist in said pharmaceutical composition is a daily dose equivalent to 150 mg to 3000 mg, usually 300 mg to 3000 mg of 6-propylamino-4,5,5 as (R)/(S)-mixture. It may also be aimed at the treatment of synucleinopathies with 6,7-tetrahydro-1,3-benzothiazol-2-amine, said daily dose being between pramipexole dihydrochloride monohydrate 0.375 mg to 45 mg. , Preferably more than 6 mg to 45 mg or 6.5 mg to 45 mg, usually 0.375 mg to 40-42 mg, preferably more than 6 mg to 40-42 mg or 6.5 mg to 40-42 mg of the corresponding (S) enantiomer. Including the daily dose, said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is also included in the pharmaceutical in dosage unit form, mixed with a pharmaceutical carrier or vehicle. Be done.

The advantageous NK1 antagonist in the pharmaceutical composition further comprises pramipexole dihydrochloride monohydrate 0.75 mg to 90 mg, preferably more than 12 mg to 90 mg or 13 mg to 90 mg, usually 0.75 mg to 80 mg, preferably Synucleinopathies with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine as racemate in daily doses corresponding to >12 mg to 80 mg or 13 mg to 80 mg 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine can also be mixed with a pharmaceutical carrier or vehicle to give a dosage unit. Included in the form of medicine.

NK1 antagonists and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine are administered as a pharmaceutical carrier or vehicle for administration for the treatment of synucleinopathies. And each of them are formulated into a pharmaceutical composition.

In the treatment of synucleinopathies, NK1 antagonists and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine are used in combination and are pharmaceutically acceptable carriers. Alternatively, the two active ingredients may be co-administered simultaneously or sequentially in admixture with a vehicle, or NK1 antagonist and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole It may be co-administered in a fixed dose combination comprising a pharmaceutical composition comprising 2-amine.

NK1 antagonist component (a) and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine component (b) are capsules, tablets, powders, cachets, suspensions. , Solutions, or any conventional oral or parenteral dosage unit forms, such as transdermal devices, can be administered separately or together.

Separately, an effective amount of the NK1 antagonist per unit form and the effective amount of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine per unit form ( When administered simultaneously or sequentially), the components are each mixed in one container with a pharmaceutical carrier or vehicle and packaged in a kit containing the NK1 antagonist, in a separate container. The 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, preferably pramipexole, can be packaged in admixture with a conventional carrier or vehicle.

The NK1 antagonist and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or pharmaceuticals thereof for co-administration for the treatment of synucleinopathies. Acceptable salts or solvates are mixed with a pharmaceutical carrier or vehicle to form the NK1 antagonist and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2. A fixed dose combination consisting of a pharmaceutical composition comprising an amine, which may be co-formulated.

The fixed dose combination ensures safe co-administration of the NK1 antagonist and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine.

As noted above, the amount of NK1 antagonist per dosage unit form should be at least the same as the dose approved for the prevention or treatment of postoperative nausea and vomiting or the prevention of chemotherapy-induced nausea and vomiting. It can be up to 6 times the dose.

According to a fourth aspect, the present invention provides, as an active ingredient, any of the above-mentioned effective amounts of the NK1 antagonist, or a pharmaceutically acceptable salt and solvate thereof (component (a)). And an effective amount per unit form of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-, as a second active ingredient, mixed with a pharmaceutical carrier or vehicle. There is provided a fixed dose combination comprising a pharmaceutical composition in a dosage unit form containing an amine (component (b)).

Advantageously, said NK1 antagonist component (a) is per unit form at least as much as the dose approved for the prevention and treatment of postoperative nausea and vomiting or for the prevention of chemotherapy-induced nausea and vomiting. Is the amount of.

The NK1 antagonist component (a) is present in the fixed dose combination in an amount of 1 μg to 600 mg, usually 1 mg to 600 mg or 1 mg to 300 mg per unit form, 6-propylamino-4,5,6,7. The tetrahydro-1,3-benzothiazol-2-amine component (b) is present in the fixed dose combination in amounts of 0.125 mg to 3000 mg per unit form.

In particular, according to this fourth aspect, the invention provides
Mixed with a pharmaceutical carrier or vehicle,
(A) an amount of NK1 antagonist per unit form of 1 μg to 600 mg;
(B) selected from the group consisting of pramipexole dihydrochloride monohydrate in an amount corresponding to 0.125 mg to 45 mg, preferably 0.125 mg to 40-42-42 mg, of pramipexole or a pharmaceutically acceptable salt thereof. 6-Propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine; corresponding to pramipexole dihydrochloride monohydrate 0.25 mg to 90 mg, preferably 0.25 mg to 80 mg Racemic amount or a pharmaceutically acceptable salt thereof; per unit form corresponding to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate, preferably 0.125 mg to 40-42 mg. There is provided a pharmaceutical composition in a dosage unit form comprising (R)/(S) mixture in an amount of 50 mg to 3000 mg per unit form, including an amount of (S) enantiomer.

Preferably, the NK1 antagonist dose/unit form has been shown or approved for the prevention or treatment of post-operative nausea and vomiting or the prevention of chemotherapy-induced nausea and vomiting in children. Alternatively, the dose may be at least about the same as the adult dose and up to 6 times the dose.

According to a first embodiment, the NK1 antagonist component (a) is aprepitant in an amount per IR unit form from 10 mg to 125 mg or lorapitant in a dose per unit form from 15 mg to 270 mg, 6-propylamino- The 4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine has the composition (in the fixed dose combination with the NKl antagonist) in the amount of 0.125 mg to 1500 mg per IR unit form. It exists in things.

Preferably, in the pharmaceutical composition, the NK1 antagonist component (a) is an aprepitant with an IR dose ranging from 10 mg to 125 mg in an IR formulation.

The dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine component (b) per IR unit form was (when combined with NK1 antagonist component (a) Depending on the safety and tolerability, it is usually 0.125 mg to 1500 mg, advantageously 1.6 mg to 1500 mg, preferably 1.625 mg to 1500 mg.

Said dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine per IR unit form was safe (when combined with an NK1 antagonist) and tolerated. It is usually in the range of 1.5 mg to 1500 mg depending on the sex.

According to this first embodiment, the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine component (b) of the fixed-dose combination drug is pramipexole or its When it is a pharmaceutically acceptable salt or solvate, the dose range per IR unit form depends on its safety (when combined with the NK1 antagonist) and tolerability, pramipexole dihydrochloride monohydrate. Japanese equivalent of 0.125 mg to 30 mg, usually 0.125 mg to 22.5 mg, 0.125 mg to 11.25 mg, preferably 0.125 mg to 30 mg or 0.125 mg to 20-21 mg, usually 0.125 mg to 10 mg. Will. Generally, when the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate in an IR formulation, the dose range is ( Depending on the safety and tolerability (when combined with the NK1 antagonist) 0.125 mg to 30 mg or 0.125 mg to 20-21 mg per IR unit form, usually 0.125 mg to 10 mg. When the NK1 antagonist is aprepitant, the aprepitant dose per IR unit form in combination with pramipexole dihydrochloride monohydrate will be 10 mg to 125 mg aprepitant.

If the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine component (b) of the fixed dose combination is a racemate, the dose per IR unit form The range is 0.25 mg to 45 mg, preferably 0.25 mg to 40-42 mg, thus corresponding to pramipexole dihydrochloride monohydrate 0.125 mg to 22.5 mg, preferably 0.125 mg to 20-21 mg. Containing (S)-enantiomer in an amount per unit form, (R)-6-propylamino-4 in an amount per unit form corresponding to 0.125 mg to 20-21 mg of pramipexole dihydrochloride monohydrate. , 5,6,7-Tetrahydro-1,3-benzothiazol-2-amine.

The 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine component (b) of the fixed dose combination drug is an (R)/(S)-mixture in an IR formulation. , The dose range per IR unit corresponds to 0.125 mg to 22.5 mg of pramipexole dihydrochloride monohydrate, preferably 0.125 mg to 20-21 mg of (S)-mirror image per unit form. Including the isomer amount, it will be 50 mg to 1500 mg, and therefore the amount per unit form corresponding to pramipexole dihydrochloride monohydrate 0.125 mg to 22.5 mg, preferably 0.125 mg to 20-21 mg ( S)-enantiomer and in an amount per unit form corresponding to 50 mg to 1500 mg (0.125 mg to 22.5 mg, preferably 0.125 mg to 20-21 mg) of pramipexole dihydrochloride monohydrate. (R)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine.

The dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine component (b) per ERRR unit form was (when combined with the NK1 antagonist component (a)) Depending on the safety and tolerability, it is usually 0.375 mg to 3000 mg, advantageously more than 4.5 mg to 3000 mg, preferably 6.5 mg to 3000 mg.

The 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine component (b) of the fixed dose combination drug is a slow-release composition and a transdermal therapeutic system such as a transdermal therapeutic system. When pramipexole or a pharmaceutically acceptable salt or solvate thereof in an ER formulation, including a skin patch, its amount per unit form is well tolerated (when combined with an NK1 antagonist). Accordingly, pramipexole dihydrochloride monohydrate 1.5 mg to 45 mg, 3 mg to 45 mg, or 3 mg to 22.5 mg, preferably 1.5 mg to 40-42 mg, 3 mg to 40-42 mg, or 3 mg to 20-21 mg. It corresponds to the range of. In particular, when the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate, the dose range/unit form is 1. It will be 5 mg to 45 mg, usually 3 mg to 45 mg, or 3 mg to 22.5 mg, preferably 1.5 mg to 40-42 mg, usually 3 mg to 40-42 mg or 3 mg to 20-21 mg.

The 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine component (b) of the fixed dose combination drug is a slow-release composition and a transdermal therapeutic system such as a transdermal therapeutic system. In the case of an (R)/(S)-mixture in an ER formulation, including a skin patch, the dose range/ER unit is pramipexole dihydrochloride depending on tolerability (when combined with an NK1 antagonist). Salt monohydrate 3 mg-45 mg, preferably more than 4.5 mg-45 mg, more than 6 mg-45 or 6.5 mg-45 mg, usually 3 mg-40-42 mg, preferably more than 4.5 mg-40-42 mg, more than 6 mg- Including an amount of (S)-enantiomer per unit form corresponding to 40-42 or 6.5 mg to 40-42 mg results in 150 mg-3000 mg or 300 mg-3000 mg, thus a dose range of, for example, 3-40-42 mg. In the case of pramipexole dihydrochloride monohydrate 3 mg to 45 mg, preferably 3 mg to 40-42 mg, corresponding to the amount per unit form of the (S)-enantiomer, and pramipexole dihydrochloride monohydrate 150 mg ˜3000 mg or 300 mg to 3000 mg (subtract 3 mg to 45 mg, preferably 3 mg to 40-42 mg) in an amount per unit form of (R)-6-propylamino-4,5,6,7-tetrahydro- Contains 1,3-benzothiazol-2-amine.

If the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine component (b) of the fixed dose combination is a racemate, the dose per ER unit type The range is 6 mg to 90 mg of pramipexole dihydrochloride monohydrate, preferably more than 9 mg to 90 mg, more than 12 mg to 90 mg or 13 mg to 90 mg, usually 6 mg to 80 mg, depending on tolerability when combined with an NK1 antagonist. , Preferably greater than 9 mg to 80 mg, corresponding to a range selected from the group consisting of more than 12 mg to 80 or 13 mg to 80 mg, and thus, for example, in the case of a dose range of 6 to 80 mg, for example pramipexole dihydrochloride. Containing an amount of the (S) enantiomer per unit form corresponding to monohydrate 3 mg to 45 mg, preferably 3 mg to 40-42 mg, pramipexole dihydrochloride monohydrate 3 mg to 45 mg, preferably 3 mg to 40 It contains an amount of (R)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine per unit form corresponding to -42 mg.

Specific amounts per unit form of NK1 antagonist and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine active ingredient respectively, in particular said component (a) and said component The amount per unit form subrange of (b) is the "NK1 antagonist component (a)" and the "6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine component. (B)” section.

If the NK1 antagonist is aprepitant, the dose/unit form will be in the range 10 mg to 250 mg.

When the NK1 antagonist is lorapitant, the dose per unit form in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is , 30 mg to 270 mg.

Formulations For the intended use in the treatment of synucleinopathies in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, a NK1 antagonist is a pharmaceutical composition Formulated into a pharmaceutical composition, the NK1-antagonist is mixed with a pharmaceutical carrier or vehicle. For said treatment also 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is formulated into a pharmaceutical composition, said 6-propylamino-4 ,5,6,7-Tetrahydro-1,3-benzothiazol-2-amine is mixed with a pharmaceutical carrier or vehicle.

In the pharmaceutical composition of the present invention for oral, subcutaneous, intravenous, transdermal or topical administration, the active ingredient is preferably administered in the form of a dosage unit mixed with a classic pharmaceutical carrier or vehicle as described above. To be done.

The dose, that is, the amount of the active ingredient in a single dose administered to a patient (amount per dosage unit form) greatly varies depending on the age, weight, and health condition of the patient. This dosage is administered at a dose of 1 μg to 600 mg, usually 1 mg to 600 mg or 1 mg to 300 mg, depending on the efficacy of each NK1 antagonist and the patient's age, and pramipexole dihydrochloride monohydrate depending on the patient's age. Each of the effective amounts of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine corresponding to 0.125 mg to 45 mg, preferably 0.125 mg to 40-42 mg of Depending on the strength of the dose of each of the components, it includes administration of 1 to 3 times daily by intravenous, subcutaneous, oral or transdermal administration.

When the NK1 antagonist is aprepitant, the dose is in the range of 10 mg to 250 mg, and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is pramipexole dihydrochloride. In the case of salt monohydrate, the dosage is in the range of 0.125 mg to 45 mg, preferably 0.125 mg to 40-42 mg.

When the NK1 antagonist is lorapitant, the dose is in the range of 15 mg to 270 mg, and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is pramipexole dihydrochloride. In the case of salt monohydrate, the dosage is in the range of 0.125 mg to 45 mg, preferably 0.125 mg to 40-42 mg.

The pharmaceutical composition of the present invention, as described above, takes the unit form formulated with a classic excipient suitable for different administration methods. Said unit form is for example prepared according to the prior art which allows the formulation of the IR form of the NK1 antagonist and the same unit form of the ER form of pramipexole dihydrochloride monohydrate. Particularly advantageous are tablets, multi-score tablets, multilayer tablets, coated tablets), orally disintegrating tablets, sustained release tablets, hard or soft capsules, multi-compartment capsules, sustained release capsules, patches for transdermal administration , Liquid oral solutions, syrups or suspensions in the unit dosage form, and formulations in the form of vials for intravenous or subcutaneous administration.

The pharmaceutical composition may be formulated in an oral unit form such as tablets or gelatin capsules and may be formulated as 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or NK1 antagonist. Or both active substances are, for example, diluents such as cellulose, dextrose, lactose, mannitol, sorbitol or sucrose; lubricants such as acids, calcium stearate or magnesium stearate, polyethylene glycol, silica, or talc; and if desired. And mixed with a carrier or vehicle that may include a binder such as magnesium aluminum silicate, gelatin, methyl cellulose, sodium carboxymethyl cellulose, or polyvinylpyrrolidone.

The oral unit form may be tablets coated with sucrose or various polymers for immediate release, or the tablets may be carriers such as acrylic acid and methacrylic acid polymers and copolymers; cellulose derivatives such as hydroxypropylethyl cellulose; Alternatively, the activity is gradually released by gradually releasing a predetermined amount of the NK1 antagonist or 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or both active ingredients. It can be manufactured using other suitable materials that extend or delay. Oral formulations are in the form of capsules that allow sustained release of the NK1 antagonist or 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine or both active ingredients. Very good.

The oral unit form may be a tablet or capsule in which one of the active ingredients is an IR formulation and the other is an ER formulation. For example, the unit forms include aprepitant or lorapitant in the IR formulation and pramipexole dihydrochloride monohydrate in the ER formulation, in amounts per unit form as described above, respectively.

The pharmaceutical composition can also be formulated in TTS, such as a patch formulation, where the active ingredient or mixture of active ingredients is D-sorbitol, gelatin, kaolin, methylparaben, polysorbate 80, propylene glycol, propylparaben, povidone. , Sodium carboxymethylcellulose, sodium polyacrylate, tartaric acid, titanium dioxide, and purified water. Patch formulations may also contain skin permeation enhancers such as lactate esters (eg, lauryl lactate), triacetin or diethylene glycol monoethyl ether.

In the above pharmaceutical composition, the preferred NK1 antagonist active ingredient is aprepitant, fosaprepitant, lorapitant or netupitant-300/pslonosetron-0.5, preferred 6-propylamino-4,5,6,7. The tetrahydro-1,3-benzothiazol-2-amine active ingredient is pramipexole base or its dihydrochloride monohydrate.

Thus, for example, an amount per unit form of 0.125 mg to 30 mg or 1.5 mg to 22.5 mg, usually 1.5 mg to 11.25 mg, preferably 0.125 mg to 20 mg, usually 1.5 mg to 10 mg in an IR formulation. , Or 1.5 mg to 45 mg, preferably 3 mg to 22.5 mg, 1.5 mg to 40-42 mg, usually 3 mg to 20-21 mg, in an ER formulation administered in a daily dose of 1.5 mg to 45 mg, preferably 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, preferably pramipexole dihydrochloride monohydrate, in an amount of 1.5 mg to 40-42 mg per dosage unit form. The pharmaceutical composition according to the invention, which is administered chronically in combination with a solvate, is preferably 10 mg to 250 mg of aprepitant in the formulation, which is administered once a day; or aprepitant, administered once a day. The formulation comprises 15 mg to 270 mg of lorapitant per unit form.

In the case of children or obese patients, the daily dose of NK1 antagonist will be determined based on body weight. Thus, for example, aprepitant may be administered at a daily dose of 0.16 mg/kg to 4.2 mg/kg and lorapitant may be administered at a daily dose of 0.25 mg/kg to 4.5 mg/kg.

[Example 1]
The ability of NK1 antagonists to prevent the adverse effects of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine in humans was tested.

A Phase I study was conducted in subjects receiving oral pramipexole dihydrochloride monohydrate ("pramipexole") with or without aprepitant. The study was a single-center, single-blind, placebo-controlled trial.

The purpose of this study was to demonstrate that aprepitant can safely attenuate the gastrointestinal side effects of pramipexole administered at and above the therapeutic dose.

To enroll in the study, participants (18-60 years old) must be healthy, refrain from drinking xanthine, quinine and caffeine containing beverages and refrain from prolonged intensive physical exercise during the study. Was needed. All subjects signed an informed consent form indicating their understanding of the purpose and procedure required for the study and their willingness to participate in the study and comply with the study procedures and restrictions. The important criteria for excluding subjects from enrollment in the study were:
1. A clinically relevant acute or chronic disease that can interfere with the safety of the subject, expose it to excessive risk, or interfere with the purpose of the study during the trial.
2. A history or presence of gastrointestinal, hepatic, or renal diseases or other conditions known to interfere with the absorption, distribution, metabolism or excretion of a drug.
3. History of substance abuse, known substance dependence, or positive test for substance abuse or alcohol.
4. A history of drugs or other serious allergies.
5. ECG changes including QT interval prolongation and congenital long QT syndrome. Electrolyte abnormalities (eg, hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias, or other conditions that lead to QT prolongation.
6. Treatment with centrally active drugs or with drugs that affect peripheral cholinergic transmission within 3 months of study registration.
7. Smokers (excluding subjects who stopped smoking more than one year before enrollment in the study).
8. Excessive daily consumption of xanthine-containing beverages (ie, caffeine above 500 mg/day).
9. Ingestion of study drug within 30 days after study registration.

After enrollment in the study, participants were orally dosed with pramipexole (ranging from 1.25 mg to 20 mg) and placebo once daily in the morning with increasing dose. Dose escalation was discontinued when the subject reached the first intolerable dose (FID-1). The first intolerable dose (FID) was defined as follows.
-One episode of vomiting; or-Two episodes of nausea; or-One episode of severe nausea.

Following the washout period, participants were administered pramipexole with aprepitant (at a dose of 10 mg to 250 mg of aprepitant, starting at 10 mg, increased to 250 mg as needed to delay the onset of intolerance) and subjects Subjects continued to receive aprepitant with increasing doses of pramipexole until the second intolerant dose (FID-2) was reached. Subjects were followed for up to 8 hours on each study day for tolerability and safety.

The results showed that the combined administration of aprepitant and pramipexole allowed a tolerable increase in the pramipexole dose, with higher tolerability of the pramipexole dose than administration of pramipexole alone.

[Example 2]
A Phase I study was conducted in subjects receiving a single oral dose of pramipexole dihydrochloride monohydrate ("Pramipexole") with or without a single oral dose of aprepitant. This study was a single-center, single-blind study.

The purpose of this study was to determine whether aprepitant administered pramipexole at or above the dose approved for the treatment of Parkinson's disease or shown to be effective in the treatment of depression in clinical trials. It was to demonstrate that gastrointestinal side effects can be safely attenuated.

To enroll in the study, participants followed the following inclusion/exclusion key criteria.

Main participation criteria 1. Both male and female subjects aged 20-45 years.
2. Women of childbearing potential may agree to abstinence, or the following medically acceptable forms of contraception from screening to 14 days after the study: condom with spermicide jelly, spermicide It is necessary to agree to use two of a diaphragm or surgical cap with jelly, or an intrauterine device (IUD). Women whose male spouse has undergone vasectomy should agree to use another form of medically acceptable contraception. The subject must agree to practice the above birth control method for 14 days after the last visit as a safety precaution.
3. Women without childbirth defined as surgically infertile (hysterectomy, bilateral ovariectomy, or bilateral salpingo-ligation) or at least 12 months after menopause Does not require contraception during the test. The reason for this must be stated in the source document.
4. Men with a female spouse of childbearing potential must agree to use a highly effective and medically acceptable form of contraception from the screening period to 14 days after the study termination visit. Men with female spouses of childbearing potential should agree to use condoms with spermicides over the same period. Male subjects should agree to practice the above birth control method for 14 days after the last visit as a safety precaution.
5. Subjects should be healthy as judged by their personal and family psychological history, physical examination, electrocardiogram (ECG), vital signs, and medical history, including clinical examination results. A subject with a medical abnormality may be included only if the examiner or designee believes that the abnormality does not pose a significant additional risk to the subject's health or interfere with the purpose of the study.
6. Subjects should be able to clearly and reliably communicate changes in their medical condition.
7. Subjects with a body mass index (BMI) of 19.0 to 32.0 kg/m ² (including both sexes).
8. Subjects who can swallow multiple tablets or capsules at the same time.
9. Subjects are required to sign an informed consent form that indicates their understanding of the objectives and procedures required for the study and their willingness to participate in the study and comply with study procedures and restrictions.

Main exclusion criteria:
The criteria for excluding subjects from enrollment in the study were:
1. A clinically relevant acute or chronic disease that can interfere with the safety of the subject, expose it to excessive risk, or interfere with the purpose of the study during the trial.
2. A history or presence of gastrointestinal, hepatic, or renal disease or other condition known to interfere with absorption, distribution, metabolism, or excretion of the study drug.
3. History of substance abuse, known substance dependence, or positive test for substance abuse or alcohol.
4. A history of drugs or other serious allergies.
5. Known hypersensitivity to pramipexole, or ondansetron or a similar serotonin receptor antagonist, or aprepitant or a similar substance P/NK1 receptor antagonist.
5. QT interval prolongation, congenital long QT syndrome, electrolyte abnormalities (eg, hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmia, or 450 QTcF in men on day 1 of screening or prior to dosing As described above, in women, a history and/or current status of other drugs that cause QT prolongation of 470 QTcF or more or first-degree AV block.
7. Treatment with centrally acting drugs or antiemetics within 1 month of study registration.
8. Tobacco or nicotine users (excluding subjects who stopped using tobacco or nicotine more than one year prior to study registration).
9. Excessive daily consumption of xanthine-containing beverages (ie, caffeine above 500 mg/day).
10. Subjects who do not want to reduce prolonged physical exertion during the study (from screening visit to final dose of study drug).
11. Positive test results for hepatitis B surface antigen and hepatitis C antibody.
12. Positive test result of HIV 1 or 2 serum test.
13. Probability of requiring medical or dental treatment during the study period.
14. Use of prescription or over-the-counter medications within 14 days before the first day of hospitalization. Furthermore, if the period is longer than 14 days, the centrally acting medication is banned for a period equal to 5 times the drug half-life before admission (day 1).
15. Subjects are unlikely to collaborate during the study and/or are suspected to comply with investigators' opinions.
16. Unable to contact the subject in an emergency.
17. Ingestion of study drug within 30 days after study registration.
18. Shows evidence of suicidal ideation within the last 6 months, assessed by C-SSRS (Colombian Suicide Severity Rating Scale) at screening.

After enrollment in the study, participants were orally dosed with pramipexole once daily in the morning at increasing doses (study period 1). The starting dose of pramipexole was 0.5 mg and the dose was increased by 0.5 mg daily. Dose escalation was discontinued when the subject reached the first intolerable dose (FID-1). The first intolerable dose (FID) was defined as follows.
-One episode of vomiting; or-Two episodes of nausea; or-One episode of severe nausea lasting more than 1 hour (Grade 3; activities of daily living or inadequate oral calorie or fluid intake). Defined as disturbed nausea; tube feeding, complete parenteral nutrition or hospitalization required), or-three consecutive episodes of moderate nausea assessed every 4 hours (grade 2; subjectivity) Defined as symptomatic but does not interfere with activities of daily living), or-one episode of moderate diarrhea (grade 2; defined as 4-6 more bowel movements than baseline). ).

When the subject reached FID-1 with pramipexole alone, the subject was washed out for at least 5 days and then entered Study Period 2, during which time the subject started on 0.5 mg once daily for pramipexole. Oral doses were given and with oral aprepitant (80 mg), dose escalation in 0.5 mg increments until the subject again reached the intolerable dose as defined above. The FID for oral pramipexole and oral aprepitant was designated FID-2.

If the subject reached FID-2 at a dose equal to or lower than FID-1 in period 2, the subject would agree on the next day, provided that the investigator concludes that there are no safety issues and the subject agrees. , Received the same dose of pramipexole as FID-2 with a higher dose of oral aprepitant (120 mg), and in the protocol, said subject received a higher dose of oral aprepitant (120 mg) until an intolerable dose (FID2+) was reached. ) Defined that the remaining dose escalation should continue. All other provisions of the protocol are unchanged. The evaluation was the same as planned for the dose escalation date.

On each study day, subjects were followed for up to 8 hours post drug administration for AE, vital signs, ECG. In addition, a laboratory panel was obtained at screening and at the end of the test.

Four subjects were enrolled in the study. Table 1 below summarizes the demographic characteristics of the subjects.

All subjects reached FID-1 (pramipexole alone) during the study. Dose limiting toxicity was a gastrointestinal adverse event in all four subjects. During Study Period 2, all four subjects tolerated the maximum pramipexole dose allowed with the 6 mg protocol and therefore none of the subjects reached FID-2 (pramipexole plus aprepitant) .. In other words, the combined administration of pramipexole and aprepitant prevented the occurrence of dose limiting gastrointestinal adverse events associated with high doses of pramipexole. Table 2 shows the values of FID-1 (pramipexole alone) and FID-2 (combination of pramipexole and aprepitant) for each subject.

As shown in Table 3 below, the maximum tolerated dose (MTD) in period 2 was higher than the MTD in period 1 in all subjects, and MTD-2 increased more than 3-fold in 3 subjects.

Taken together, the results show that co-administration of aprepitant and pramipexole alleviates the dose-limiting gastrointestinal adverse effects reported with pramipexole alone, thus NK1 antagonists are not tolerated when administered pramipexole alone It has been shown that doses allow pramipexole to be administered to humans.

In conclusion, co-administration of aprepitant and pramipexole suppresses the development of gastrointestinal AEs associated with pramipexole alone administration, thus allowing the dose of pramipexole to be increased more than 2-fold in a safe and tolerable manner. , Can increase the effectiveness of this drug. In particular, these results indicate that the protective effect of NK1 antagonists allows safe treatment of humans with pramipexole not only within the approved dose range of pramipexole but also at doses higher than the maximum recommended dose. ing.

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Claims (23)

A method of treating synucleinopathies in a patient, wherein the patient in need thereof is treated with an effective daily dose of an NK1 antagonist and an effective daily dose of 6-propylamino-4,5,6,6. A method comprising administering in combination with 7-tetrahydro-1,3-benzothiazol-2-amine. The method of claim 1, wherein the effective daily dose of the NK1 antagonist is 1 μg to 600 mg. The method of claim 1, wherein the effective daily dose of the NK1 antagonist is 1 mg to 600 mg. The method of claim 1, wherein the NK1 antagonist is aprepitant or a pharmaceutically acceptable salt or solvate thereof. The method of claim 1, wherein the NK1 antagonist is lorapitant or a pharmaceutically acceptable salt or solvate thereof. The NK1 antagonist is aprepitant and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate. The method described in. The NK1 antagonist is an effective daily dose of aprepitant of 10 mg to 250 mg, and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is 1.5 mg. The method of claim 1, wherein the effective daily dose of pramipexole dihydrochloride monohydrate is -45 mg. The NK1 antagonist and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine are each mixed with a pharmaceutical carrier or vehicle to form the NK1 antagonist, The pharmaceutical composition according to claim 1, which is formulated in a dosage unit form containing 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine. The method described. The NK1 antagonist and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine
Each mixed with a pharmaceutical carrier or vehicle,
An amount of said NK1 antagonist per unit form of 1 μg to 600 mg;
A pharmaceutical composition in the form of a dosage unit, each containing 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine in an amount of 0.125 mg to 3000 mg per unit. The method according to claim 1, which is formulated respectively. The NK1 antagonist and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine each in an amount of 1 mg to 600 mg per unit form of the NK1 antagonist; And 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, which is pramipexole dihydrochloride monohydrate in an amount per unit form of more than 4.5 mg to 45 mg The method according to claim 1, each of which is formulated into a pharmaceutical composition in a dosage unit form comprising: The 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate in an amount per unit form of greater than 6 mg to 45 mg, The method according to claim 10. The 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is pramipexole dihydrochloride monohydrate in an amount of 6.5 mg to 45 mg per unit form. The method according to claim 10. The NK1 antagonist and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine are mixed with a pharmaceutical carrier or vehicle to give 1 μg to 600 mg per unit form. In an amount of 0.125 mg to 3000 mg per unit form of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine. 2. The method of claim 1, co-formulated with the pharmaceutical composition in dosage unit form. Administration in which the NK1 antagonist and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine comprise an amount of the NK1 antagonist per unit form of 1 μg to 600 mg. Is co-formulated into a pharmaceutical composition in unit form, wherein the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is mixed with a pharmaceutical carrier or vehicle. And selected from the group consisting of pramipexole and pharmaceutically acceptable salts and solvates thereof in an amount per unit form corresponding to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate. The method according to 1. In the composition, the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is in an amount of more than 4.5 mg to 45 mg of pramipexole dihydrochloride. 15. The method of claim 14, which is a monohydrate. In the composition, the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is used in an amount of more than 6 mg to 45 mg of pramipexole dihydrochloride monohydrate. The method according to claim 14, which is a Japanese product. In the composition, the NK1 antagonist is aprepitant in an amount of 10 mg to 250 mg per unit form, and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2- 15. The method of claim 14, wherein the amine is pramipexole dihydrochloride monohydrate in an amount per unit form of 0.125 mg to 45 mg. The synucleinopathies are Parkinson's disease, dementia with Lewy bodies, mutations in the glucocerebrosidase gene, Alzheimer's disease, Lewy body variants of Alzheimer's disease, multiple system atrophy, neurodegeneration with brain iron accumulation, and gluco. The method of claim 1, wherein the method is selected from the group consisting of Parkinson's disease associated with cerebrosidase (GBA) mutations. Mixed with a pharmaceutical carrier or vehicle,
(A) an amount of NK1 antagonist per unit form of 1 μg to 600 mg;
(B)
-Racemic form or a pharmaceutically acceptable salt thereof in an amount per unit form corresponding to 0.25 mg to 90 mg of pramipexole dihydrochloride monohydrate;
-Pramipexole dihydrochloride monohydrate in an amount corresponding to 0.125 mg to 45 mg of pramipexole or a pharmaceutically acceptable salt thereof;
An amount of (R)/(S) of 50 mg to 3000 mg per unit form, including an amount of (S) enantiomer per unit form corresponding to 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate. A pharmaceutical composition in dosage unit form, comprising 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine selected from the group consisting of mixtures. The amount of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine corresponding to pramipexole dihydrochloride monohydrate of more than 4.5 mg to 45 mg per unit form. 20. The composition of claim 19, which is pramipexole or a pharmaceutically acceptable salt thereof. Said 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine in an amount per unit form corresponding to more than 6 mg to 45 mg of pramipexole dihydrochloride monohydrate, The composition according to claim 19, which is pramipexole or a pharmaceutically acceptable salt thereof. The 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is used in an amount per unit form corresponding to pramipexole dihydrochloride monohydrate of 6.5 mg to 45 mg. 20. The composition according to claim 19, which is pramipexole or a pharmaceutically acceptable salt thereof. The NK1 antagonist is aprepitant in an amount of 10 mg to 250 mg per unit, and the 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine is 0.125 mg. 20. The composition of claim 19, which is pramipexole dihydrochloride monohydrate in an amount per unit form of -45 mg.